102 results on '"Eric Hervouet"'
Search Results
2. DHX15-independent roles for TFIP11 in U6 snRNA modification, U4/U6.U5 tri-snRNP assembly and pre-mRNA splicing fidelity
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Amandine Duchemin, Tina O’Grady, Sarah Hanache, Agnès Mereau, Marc Thiry, Ludivine Wacheul, Catherine Michaux, Eric Perpète, Eric Hervouet, Paul Peixoto, Felix G. M. Ernst, Yann Audic, Franck Dequiedt, Denis L. J. Lafontaine, and Denis Mottet
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Science - Abstract
In yeast, TFIP11 and DHX15 promote the disassembly of spliceosome complex after splicing is completed. Here the authors show that human TFIP11 functions independently of DHX15 and is required for U6 snRNA 2’-O-methylation and U4/U6.U5 tri-snRNP assembly.
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- 2021
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3. The detection of specific hypermethylated WIF1 and NPY genes in circulating DNA by crystal digital PCR™ is a powerful new tool for colorectal cancer diagnosis and screening
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Alexis Overs, Mylène Flammang, Eric Hervouet, Laurent Bermont, Jean-Luc Pretet, Borg Christophe, and Zohair Selmani
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Colorectal cancer ,Liquid biopsy ,Epigenetics ,DNA methylation ,NPY ,WIF1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background In oncology, liquid biopsy is of major relevance from theranostic point of view. The searching for mutations in circulating tumor DNA (ctDNA) in case of colorectal cancers (CRCs) allows the optimization of patient care. In this context, independent of mutation status biomarkers are required for its detection to confirm the presence of ctDNA in liquid biopsies. Indeed, the hypermethylation of NPY and WIF1 genes appear to be an ideal biomarker for the specific detection of ctDNA in CRCs. The objective of this work is to develop the research of hypermethylation of NPY and WIF1 by Crystal Digital PCR™ for the detection of ctDNA in CRCs. Methods Detection of hypermethylated NPY and WIF1 was developed on Cristal digital PCR™. Biological validation was performed from a local cohort of 22 liquid biopsies and 23 tissue samples from patients with CRC. These patients were treated at the University Hospital of Besancon (France). Results The local cohort study confirmed that NPY and WIF1 were significantly hypermethylated in tumor tissues compared to adjacent non-tumor tissues (WIF1 p
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- 2021
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4. Chemokine switch regulated by TGF-β1 in cancer-associated fibroblast subsets determines the efficacy of chemo-immunotherapy
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Angélique Vienot, Jean-René Pallandre, Elodie Renaude, Julien Viot, Adeline Bouard, Laurie Spehner, Marie Kroemer, Syrine Abdeljaoued, Bas van der Woning, Hans de Haard, Romain Loyon, Eric Hervouet, Paul Peixoto, and Christophe Borg
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fibroblast ,TGF-β ,chemo-immunotherapy ,chemokine ,cancer ,microenvironment ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Combining immunogenic cell death-inducing chemotherapies and PD-1 blockade can generate remarkable tumor responses. It is now well established that TGF-β1 signaling is a major component of treatment resistance and contributes to the cancer-related immunosuppressive microenvironment. However, whether TGF-β1 remains an obstacle to immune checkpoint inhibitor efficacy when immunotherapy is combined with chemotherapy is still to be determined. Several syngeneic murine models were used to investigate the role of TGF-β1 neutralization on the combinations of immunogenic chemotherapy (FOLFOX: 5-fluorouracil and oxaliplatin) and anti-PD-1. Cancer-associated fibroblasts (CAF) and immune cells were isolated from CT26 and PancOH7 tumor-bearing mice treated with FOLFOX, anti-PD-1 ± anti-TGF-β1 for bulk and single cell RNA sequencing and characterization. We showed that TGF-β1 neutralization promotes the therapeutic efficacy of FOLFOX and anti-PD-1 combination and induces the recruitment of antigen-specific CD8+ T cells into the tumor. TGF-β1 neutralization is required in addition to chemo-immunotherapy to promote inflammatory CAF infiltration, a chemokine production switch in CAF leading to decreased CXCL14 and increased CXCL9/10 production and subsequent antigen-specific T cell recruitment. The immune-suppressive effect of TGF-β1 involves an epigenetic mechanism with chromatin remodeling of CXCL9 and CXCL10 promoters within CAF DNA in a G9a and EZH2-dependent fashion. Our results strengthen the role of TGF-β1 in the organization of a tumor microenvironment enriched in myofibroblasts where chromatin remodeling prevents CXCL9/10 production and limits the efficacy of chemo-immunotherapy.
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- 2022
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5. Droplet digital PCR allows vector copy number assessment and monitoring of experimental CAR T cells in murine xenograft models or approved CD19 CAR T cell-treated patients
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Rafik Haderbache, Walid Warda, Eric Hervouet, Mathieu Neto da Rocha, Rim Trad, Vincent Allain, Clementine Nicod, Catherine Thieblemeont, Nicolas Boissel, Pauline Varlet, Ibrahim Yakoub Agha, Lucie Bouquet, Melanie Guiot, Fabienne Venet, Pierre Sujobert, Xavier Roussel, Paul-Oliver Rouzaire, Denis Caillot, Olivier Casasnovas, Jean Christophe Bories, Emmanuel Bachy, Sophie Caillat-Zucman, Marina Deschamps, and Christophe Ferrand
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Chimeric antigen receptor ,Droplet digital PCR ,IL-1RAP ,Tisa-cel ,Axi-cel ,Monitoring ,Medicine - Abstract
Abstract Background Genetically engineered chimeric antigen receptor (CAR) T lymphocytes are promising therapeutic tools for cancer. Four CAR T cell drugs, including tisagenlecleucel (tisa-cel) and axicabtagene-ciloleucel (axi-cel), all targeting CD19, are currently approved for treating B cell malignancies. Flow cytometry (FC) remains the standard for monitoring CAR T cells using a recombinant biotinylated target protein. Nevertheless, there is a need for additional tools, and the challenge is to develop an easy, relevant, highly sensitive, reproducible, and inexpensive detection method. Molecular tools can meet this need to specifically monitor long-term persistent CAR T cells. Methods Based on 2 experimental CAR T cell constructs, IL-1RAP and CS1, we designed 2 quantitative digital droplet (ddPCR) PCR assays. By targeting the 4.1BB/CD3z (28BBz) or 28/CD3z (28z) junction area, we demonstrated that PCR assays can be applied to approved CD19 CAR T drugs. Both 28z and 28BBz ddPCR assays allow determination of the average vector copy number (VCN) per cell. We confirmed that the VCN is dependent on the multiplicity of infection and verified that the VCN of our experimental or GMP-like IL-1RAP CAR T cells met the requirement (
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- 2021
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6. 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer
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Arnaud Blomme, Catriona A. Ford, Ernest Mui, Rachana Patel, Chara Ntala, Lauren E. Jamieson, Mélanie Planque, Grace H. McGregor, Paul Peixoto, Eric Hervouet, Colin Nixon, Mark Salji, Luke Gaughan, Elke Markert, Peter Repiscak, David Sumpton, Giovanny Rodriguez Blanco, Sergio Lilla, Jurre J. Kamphorst, Duncan Graham, Karen Faulds, Gillian M. MacKay, Sarah-Maria Fendt, Sara Zanivan, and Hing Y. Leung
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Science - Abstract
Androgen receptor (AR) signalling regulates cellular metabolism in prostate cancer. Here, the authors perform a proteomics and metabolomics characterisation of prostate cancer cells adapted to long-term resistance to AR inhibition and show rewiring of glucose and lipid metabolism, and further identify a signature associated with resistance to AR inhibition.
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- 2020
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7. Epigenetic Reprogramming of CD4+ Helper T Cells as a Strategy to Improve Anticancer Immunotherapy
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Elodie Renaude, Marie Kroemer, Christophe Borg, Paul Peixoto, Eric Hervouet, Romain Loyon, and Olivier Adotévi
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epigenetics ,CD4+ helper T cells ,plasticity ,tumor microenvironment ,immunotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Evidences highlight the role of various CD4+ helper T cells (CD4+ Th) subpopulations in orchestrating the immune responses against cancers. Epigenetics takes an important part in the regulation of CD4+ Th polarization and plasticity. In this review, we described the epigenetic factors that govern CD4+ T cells differentiation and recruitment in the tumor microenvironment and their subsequent involvement in the antitumor immunity. Finally, we discussed how to manipulate tumor reactive CD4+ Th responses by epigenetic drugs to improve anticancer immunotherapy.
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- 2021
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8. Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma
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Eric Hervouet, Paul Peixoto, Régis Delage-Mourroux, Michaël Boyer-Guittaut, and Pierre-François Cartron
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DNA methylation ,DNMT1 ,DNMT3A ,DNMT3B ,DNMT3L ,Epigenetics ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Our current view of DNA methylation processes is strongly moving: First, even if it was generally admitted that DNMT3A and DNMT3B are associated with de novo methylation and DNMT1 is associated with inheritance DNA methylation, these distinctions are now not so clear. Secondly, since one decade, many partners of DNMTs have been involved in both the regulation of DNA methylation activity and DNMT recruitment on DNA. The high diversity of interactions and the combination of these interactions let us to subclass the different DNMT-including complexes. For example, the DNMT3L/DNMT3A complex is mainly related to de novo DNA methylation in embryonic states, whereas the DNMT1/PCNA/UHRF1 complex is required for maintaining global DNA methylation following DNA replication. On the opposite to these unspecific DNA methylation machineries (no preferential DNA sequence), some recently identified DNMT-including complexes are recruited on specific DNA sequences. The coexistence of both types of DNA methylation (un/specific) suggests a close cooperation and an orchestration between these systems to maintain genome and epigenome integrities. Deregulation of these systems can lead to pathologic disorders.
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- 2018
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9. GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback
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Marine Jacquet, Eric Hervouet, Timothée Baudu, Michaël Herfs, Chloé Parratte, Jean-Paul Feugeas, Valérie Perez, Célia Reynders, Marie Ancion, Marc Vigneron, Aurélie Baguet, Michaël Guittaut, Annick Fraichard, and Gilles Despouy
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autophagy ,ATG8 ,GABARAPL1 ,cancer ,EMT ,SMAD ,Biology (General) ,QH301-705.5 - Abstract
The pathway of selective autophagy, leading to a targeted elimination of specific intracellular components, is mediated by the ATG8 proteins, and has been previously suggested to be involved in the regulation of the Epithelial–mesenchymal transition (EMT) during cancer’s etiology. However, the molecular factors and steps of selective autophagy occurring during EMT remain unclear. We therefore analyzed a cohort of lung adenocarcinoma tumors using transcriptome analysis and immunohistochemistry, and found that the expression of ATG8 genes is correlated with that of EMT-related genes, and that GABARAPL1 protein levels are increased in EMT+ tumors compared to EMT- ones. Similarly, the induction of EMT in the A549 lung adenocarcinoma cell line using TGF-β/TNF-α led to a high increase in GABARAPL1 expression mediated by the EMT-related transcription factors of the SMAD family, whereas the other ATG8 genes were less modified. To determine the role of GABARAPL1 during EMT, we used the CRISPR/Cas9 technology in A549 and ACHN kidney adenocarcinoma cell lines to deplete GABARAPL1. We then observed that GABARAPL1 knockout induced EMT linked to a defect of GABARAPL1-mediated degradation of the SMAD proteins. These findings suggest that, during EMT, GABARAPL1 might intervene in an EMT-regulatory loop. Indeed, induction of EMT led to an increase in GABARAPL1 levels through the activation of the SMAD signaling pathway, and then GABARAPL1 induced the autophagy-selective degradation of SMAD proteins, leading to EMT inhibition.
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- 2021
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10. The NMD Pathway Regulates GABARAPL1 mRNA during the EMT
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Timothée Baudu, Chloé Parratte, Valérie Perez, Marie Ancion, Stefania Millevoi, Eric Hervouet, Anne Peigney, Paul Peixoto, Alexis Overs, Michael Herfs, Annick Fraichard, Michaël Guittaut, and Aurélie Baguet
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NMD ,autophagy ,ATG8 ,GABARAPL1 ,GABARAP ,LC3 ,Biology (General) ,QH301-705.5 - Abstract
EMT is a reversible cellular process that is linked to gene expression reprogramming, which allows for epithelial cells to undergo a phenotypic switch to acquire mesenchymal properties. EMT is associated with cancer progression and cancer therapeutic resistance and it is known that, during the EMT, many stress response pathways, such as autophagy and NMD, are dysregulated. Therefore, our goal was to study the regulation of ATG8 family members (GABARAP, GABARAPL1, LC3B) by the NMD and to identify molecular links between these two cellular processes that are involved in tumor development and metastasis formation. IHC experiments, which were conducted in a cohort of patients presenting lung adenocarcinomas, showed high GABARAPL1 and low UPF1 levels in EMT+ tumors. We observed increased levels of GABARAPL1 correlated with decreased levels of NMD factors in A549 cells in vitro. We then confirmed that GABARAPL1 mRNA was indeed targeted by the NMD in a 3′UTR-dependent manner and we identified four overlapping binding sites for UPF1 and eIF4A3 that are potentially involved in the recognition of this transcript by the NMD pathway. Our study suggests that 3′UTR-dependent NMD might be an important mechanism that is involved in the induction of autophagy and could represent a promising target in the development of new anti-cancer therapies.
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- 2021
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11. Epithelial to Mesenchymal Transition History: From Embryonic Development to Cancers
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Camille Lachat, Paul Peixoto, and Eric Hervouet
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EMT ,development ,cancer ,Microbiology ,QR1-502 - Abstract
Epithelial to mesenchymal transition (EMT) is a process that allows epithelial cells to progressively acquire a reversible mesenchymal phenotype. Here, we recount the main events in the history of EMT. EMT was first studied during embryonic development. Nowadays, it is an important field in cancer research, studied all around the world by more and more scientists, because it was shown that EMT is involved in cancer aggressiveness in many different ways. The main features of EMT’s involvement in embryonic development, fibrosis and cancers are briefly reviewed here.
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- 2021
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12. EZH2 and KDM6B Expressions Are Associated with Specific Epigenetic Signatures during EMT in Non Small Cell Lung Carcinomas
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Camille Lachat, Diane Bruyère, Amandine Etcheverry, Marc Aubry, Jean Mosser, Walid Warda, Michaël Herfs, Elodie Hendrick, Christophe Ferrand, Christophe Borg, Régis Delage-Mourroux, Jean-Paul Feugeas, Michaël Guittaut, Eric Hervouet, and Paul Peixoto
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epigenetics ,epithelial mesenchymal transition ,H3K27me3 ,EZH2 ,KDM6B ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The role of Epigenetics in Epithelial Mesenchymal Transition (EMT) has recently emerged. Two epigenetic enzymes with paradoxical roles have previously been associated to EMT, EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 (PRC2) Subunit), a lysine methyltranserase able to add the H3K27me3 mark, and the histone demethylase KDM6B (Lysine Demethylase 6B), which can remove the H3K27me3 mark. Nevertheless, it still remains unclear how these enzymes, with apparent opposite activities, could both promote EMT. In this study, we evaluated the function of these two enzymes using an EMT-inducible model, the lung cancer A549 cell line. ChIP-seq coupled with transcriptomic analysis showed that EZH2 and KDM6B were able to target and modulate the expression of different genes during EMT. Based on this analysis, we described INHBB, WTN5B, and ADAMTS6 as new EMT markers regulated by epigenetic modifications and directly implicated in EMT induction.
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- 2020
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13. From 1957 to Nowadays: A Brief History of Epigenetics
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Paul Peixoto, Pierre-François Cartron, Aurélien A. Serandour, and Eric Hervouet
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epigenetics ,history ,DNA methylation ,histones ,epitranscriptomics ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Due to the spectacular number of studies focusing on epigenetics in the last few decades, and particularly for the last few years, the availability of a chronology of epigenetics appears essential. Indeed, our review places epigenetic events and the identification of the main epigenetic writers, readers and erasers on a historic scale. This review helps to understand the increasing knowledge in molecular and cellular biology, the development of new biochemical techniques and advances in epigenetics and, more importantly, the roles played by epigenetics in many physiological and pathological situations.
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- 2020
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14. The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment
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Elodie Renaude, Marie Kroemer, Romain Loyon, Delphine Binda, Christophe Borg, Michaël Guittaut, Eric Hervouet, and Paul Peixoto
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epigenetic modifications ,th17 cells ,tumor microenvironment ,til ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Th17 cells represent a subset of CD4+ T cells characterized by the master transcription factor RORγt and the production of IL-17. Epigenetic modifications such as post-translational histone modifications and DNA methylation play a key role in Th17 cell differentiation and high plasticity. Th17 cells are highly recruited in many types of cancer and can be associated with good or bad prognosis. Here, we will review the remodeling of the epigenome induced by the tumor microenvironment, which may explain Th17 cell predominance. We will also discuss the promising treatment perspectives of molecules targeting epigenetic enzymes to remodel a Th17-enriched tumor microenvironment.
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- 2020
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15. Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: A View on Paradoxical Roles of KDM6B and EZH2
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Camille Lachat, Michaël Boyer-Guittaut, Paul Peixoto, and Eric Hervouet
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cancer ,EMT ,metastasis ,epigenetics ,KDM6B ,EZH2 ,H3K27 ,Genetics ,QH426-470 ,Biotechnology ,TP248.13-248.65 - Abstract
EMT (epithelial to mesenchymal transition) is a plastic phenomenon involved in metastasis formation. Its plasticity is conferred in a great part by its epigenetic regulation. It has been reported that the trimethylation of lysine 27 histone H3 (H3K27me3) was a master regulator of EMT through two antagonist enzymes that regulate this mark, the methyltransferase EZH2 (enhancer of zeste homolog 2) and the lysine demethylase KDM6B (lysine femethylase 6B). Here we report that EZH2 and KDM6B are overexpressed in numerous cancers and involved in the aggressive phenotype and EMT in various cell lines by regulating a specific subset of genes. The first paradoxical role of these enzymes is that they are antagonistic, but both involved in cancer aggressiveness and EMT. The second paradoxical role of EZH2 and KDM6B during EMT and cancer aggressiveness is that they are also inactivated or under-expressed in some cancer types and linked to epithelial phenotypes in other cancer cell lines. We also report that new cancer therapeutic strategies are targeting KDM6B and EZH2, but the specificity of these treatments may be increased by learning more about the mechanisms of action of these enzymes and their specific partners or target genes in different cancer types.
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- 2018
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16. ATG9A Is Overexpressed in Triple Negative Breast Cancer and Its In Vitro Extinction Leads to the Inhibition of Pro-Cancer Phenotypes
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Aurore Claude-Taupin, Leïla Fonderflick, Thierry Gauthier, Laura Mansi, Jean-René Pallandre, Christophe Borg, Valérie Perez, Franck Monnien, Marie-Paule Algros, Marc Vigneron, Pascale Adami, Régis Delage-Mourroux, Paul Peixoto, Michael Herfs, Michaël Boyer-Guittaut, and Eric Hervouet
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ATG9A ,autophagy ,triple negative breast cancer ,MDA-MB-436 ,shRNA ,CRISPR/Cas9 ,Cytology ,QH573-671 - Abstract
Early detection and targeted treatments have led to a significant decrease in mortality linked to breast cancer (BC), however, important issues need to be addressed in the future. One of them will be to find new triple negative breast cancer (TNBC) therapeutic strategies, since none are currently efficiently targeting this subtype of BC. Since numerous studies have reported the possibility of targeting the autophagy pathway to treat or limit cancer progression, we analyzed the expression of six autophagy genes (ATG9A, ATG9B, BECLIN1, LC3B, NIX and P62/SQSTM1) in breast cancer tissue, and compared their expression with healthy adjacent tissue. In our study, we observed an increase in ATG9A mRNA expression in TNBC samples from our breast cancer cohort. We also showed that this increase of the transcript was confirmed at the protein level on paraffin-embedded tissues. To corroborate these in vivo data, we designed shRNA- and CRISPR/Cas9-driven inhibition of ATG9A expression in the triple negative breast cancer cell line MDA-MB-436, in order to determine its role in the regulation of cancer phenotypes. We found that ATG9A inhibition led to an inhibition of in vitro cancer features, suggesting that ATG9A can be considered as a new marker of TNBC and might be considered in the future as a target to develop new specific TNBC therapies.
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- 2018
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17. DNA Methylation and Apoptosis Resistance in Cancer Cells
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Pierre-François Cartron, François Marie Vallette, Eric Hervouet, and Mathilde Cheray
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apoptosis ,DNA methylation ,cancer ,epigenetic ,Cytology ,QH573-671 - Abstract
Apoptosis is a cell death programme primordial to cellular homeostasis efficiency. This normal cell suicide program is the result of the activation of a cascade of events in response to death stimuli. Apoptosis occurs in normal cells to maintain a balance between cell proliferation and cell death. A deregulation of this balance due to modifications in the apoptosic pathway leads to different human diseases including cancers. Apoptosis resistance is one of the most important hallmarks of cancer and some new therapeutical strategies focus on inducing cell death in cancer cells. Nevertheless, cancer cells are resistant to treatment inducing cell death because of different mechanisms, such as DNA mutations in gene coding for pro-apoptotic proteins, increased expression of anti-apoptotic proteins and/or pro-survival signals, or pro-apoptic gene silencing mediated by DNA hypermethylation. In this context, aberrant DNA methylation patterns, hypermethylation and hypomethylation of gene coding for proteins implicated in apoptotic pathways are possible causes of cancer cell resistance. This review highlights the role of DNA methylation of apoptosis-related genes in cancer cell resistance.
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- 2013
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18. Proximity Ligation In situ Assay is a Powerful Tool to Monitor Specific ATG Protein Interactions following Autophagy Induction.
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Thierry Gauthier, Aurore Claude-Taupin, Régis Delage-Mourroux, Michaël Boyer-Guittaut, and Eric Hervouet
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Medicine ,Science - Abstract
Macroautophagy is a highly regulated intracellular degradation process which has been extensively studied over the last decade. This pathway has been initially described as a non selective process inducing the degradation of parts of the cytoplasm as well as organelles at random. Nevertheless, over the last few years, new research highlighted the existence of a more selective autophagy pathway specifically recruiting some organelles or aggregates to the autophagosomes in order to induce their degradation. These selective autophagy pathways such as aggrephagy, mitophagy, pexophagy or xenophagy, involve the intervention of a cargo, the material to be degraded, cargo adapters, the molecules allowing the recruitment of the cargo to the autophagosome, and the proteins of the ATG8 family which link the cargo adapters to the autophagosome. One of the main questions which now remain is to develop new techniques and protocols able to discriminate between these different types of induced autophagy. In our work, we studied the possibility to use the P-LISA technique, which has been recently developed to study endogenous in vivo protein interactions, as a new technique to characterize the ATG proteins specifically involved in bulk or selective autophagy. In this manuscript, we indeed demonstrate that this technique allows the study of endogenous ATG protein interactions in cells following autophagy induction, but more interestingly that this technique might be used to characterize the ATG proteins involved in selective autophagy.
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- 2015
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19. Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells.
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Eric Hervouet, Lisenn Lalier, Emilie Debien, Mathilde Cheray, Audrey Geairon, Hélène Rogniaux, Delphine Loussouarn, Stéphane A Martin, François M Vallette, and Pierre-François Cartron
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Medicine ,Science - Abstract
Global DNA hypomethylation is a hallmark of cancer cells, but its molecular mechanisms have not been elucidated. Here, we show that the disruption of Dnmt1/PCNA/UHRF1 interactions promotes a global DNA hypomethylation in human gliomas. We then demonstrate that the Dnmt1 phosphorylations by Akt and/or PKC abrogate the interactions of Dnmt1 with PCNA and UHRF1 in cellular and acellular studies including mass spectrometric analyses and the use of primary cultured patient-derived glioma. By using methylated DNA immunoprecipitation, methylation and CGH arrays, we show that global DNA hypomethylation is associated with genes hypomethylation, hypomethylation of DNA repeat element and chromosomal instability. Our results reveal that the disruption of Dnmt1/PCNA/UHRF1 interactions acts as an oncogenic event and that one of its signatures (i.e. the low level of mMTase activity) is a molecular biomarker associated with a poor prognosis in GBM patients. We identify the genetic and epigenetic alterations which collectively promote the acquisition of tumor/glioma traits by human astrocytes and glial progenitor cells as that promoting high proliferation and apoptosis evasion.
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- 2010
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20. CD8+ CD226high T cells in liver metastases dictate the prognosis of colorectal cancer patients treated with chemotherapy and radical surgery
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Julien Viot, Syrine Abdeljaoued, Angélique Vienot, Evan Seffar, Laurie Spehner, Adeline Bouard, Kamal Asgarov, Jean-René Pallandre, Elodie Renaude, Elodie Klajer, Chloé Molimard, Franck Monnien, Frederic Bibeau, Celia Turco, Bruno Heyd, Paul Peixoto, Eric Hervouet, Romain Loyon, Alexandre Doussot, Christophe Borg, and Marie Kroemer
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Infectious Diseases ,Immunology ,Immunology and Allergy - Abstract
CD226 has been reported to participate in the rescue of CD8+ T cell dysfunction. In this study, we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes (TILs) derived from colorectal cancer (CRC) liver metastases treated with chemotherapy and radical surgery. TILs from 43 metastases were isolated and analyzed ex vivo using flow cytometry. CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry. Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets. CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors. CD226 on CD8+ T cells was not specifically coexpressed with other immune checkpoints, such as PD1, TIGIT, and TIM3, in liver metastases. Multivariate Cox regression analysis revealed CD226 expression on CD8+ T cells to be an independent prognostic factor (p = 0.003), along with CD3 density at invasion margins (p = 0.003) and TIGIT expression on CD4+ T cells (p = 0.019). CD155 was not associated with the prognostic value of CD226. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors. Downregulation of CD226 on CD8+ TILs in the liver microenvironment was restored by IL15 treatment. Overall, CD226 expression on liver metastasis-infiltrating CD8+ T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.
- Published
- 2023
21. Distinct Regulation of EZH2 and its Repressive H3K27me3 Mark in Polyomavirus-Positive and -Negative Merkel Cell Carcinoma
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Marie-Alice Durand, Aurélie Drouin, Alice Mouchard, Laurine Durand, Clara Esnault, Patricia Berthon, Anne Tallet, Yannick Le Corre, Ewa Hainaut-Wierzbicka, Astrid Blom, Philippe Saiag, Nathalie Beneton, Guido Bens, Charlee Nardin, François Aubin, Monica Dinulescu, Christine Collin, Gaëlle Fromont-Hankard, Bernard Cribier, Sara Laurent-Roussel, Kristof Cokelaere, Roland Houben, David Schrama, Paul Peixoto, Eric Hervouet, Kamel Bachiri, Diala Kantar, Etienne Coyaud, Serge Guyétant, Mahtab Samimi, Antoine Touzé, and Thibault Kervarrec
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Cell Biology ,Dermatology ,Molecular Biology ,Biochemistry - Published
- 2023
22. Data from Folate Supplementation Limits the Aggressiveness of Glioma via the Remethylation of DNA Repeats Element and Genes Governing Apoptosis and Proliferation
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Pierre-Francois Cartron, Francois M. Vallette, Jean Menanteau, Jeremie Charbord, Loic Campion, Emilie Debien, and Eric Hervouet
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Purpose: We have investigated whether the folate supplementation could be used to limit the aggressiveness of glioma through the DNA remethylation because (a) the cancer genome is characterized by a low level of DNA methylation (or 5-methylcytosine, 5 mC); and (b) folate is the main generator of S-adenosyl-methionine, the methyl donor molecule in the DNA methylation reaction catalyzed by the DNA methyltranferases.Experimental Design: The effects of folate supplementations were analyzed on the global DNA methylation status, the methylation status of DNA repeat element, the sensitivity of temozolomide-induced apoptosis, and the proliferation index of glioma cells. Finally, we analyzed whether the DNA methylation level could be used as a prognostic factor and/or a biomarker in an antiglioma therapy using folate supplementation as an adjuvant.Results: Our data show that gliomagenesis is accompanied by a reduction in 5 mC levels and that this low level of 5 mC is a poor prognostic factor in Glioblastoma Multiforme patients. We also show that folate supplementation enhanced the DNA remethylation through the Sp1/Sp3-mediated transcriptional up-regulation of genes coding for Dnmt3a and Dnmt3b proteins, two de novo methyltranferases. Finally, we show that the folate-induced DNA methylation limits proliferation and increases the sensitivity to temozolomide-induced apoptosis in glioma cells through methylation of the genes implicated in these processes (PDGF-B, MGMT, survivin, and bcl-w).Conclusion: This study suggests that folate supplementation could be a promising adjuvant for the future design of antiglioma therapies in preclinical and/or clinical studies.
- Published
- 2023
23. Supplementary Information from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
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Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
Figures S1-S2-S3 + Suppl. Fig. legends + Suppl. Methods
- Published
- 2023
24. Supplementary Data 3 from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
Pathway Enrichment_RNASeq
- Published
- 2023
25. Supplementary Data from Folate Supplementation Limits the Aggressiveness of Glioma via the Remethylation of DNA Repeats Element and Genes Governing Apoptosis and Proliferation
- Author
-
Pierre-Francois Cartron, Francois M. Vallette, Jean Menanteau, Jeremie Charbord, Loic Campion, Emilie Debien, and Eric Hervouet
- Abstract
Supplementary Data from Folate Supplementation Limits the Aggressiveness of Glioma via the Remethylation of DNA Repeats Element and Genes Governing Apoptosis and Proliferation
- Published
- 2023
26. Supplementary Data 1 from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
Proteomics_CRPC
- Published
- 2023
27. Supplementary Data 4 from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
SLFN5_binding sites
- Published
- 2023
28. Supplementary Data 2 from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
RNASeq_SLFN5 KO
- Published
- 2023
29. Supplementary Data 5 from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
ATF4_binding sites
- Published
- 2023
30. Supplementary Data 6 from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
List of antibodies
- Published
- 2023
31. Data from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
-
Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three in vivo, androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. In vivo, SLFN5 depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC.Significance:This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer.
- Published
- 2023
32. Supplementary Data 7 from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
List of primers
- Published
- 2023
33. Table S1 from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
-
Hing Y. Leung, Arnaud Blomme, Sara Zanivan, Martin E. Gleave, David Sumpton, Luke Gaughan, Ladan Fazli, Gillian M. MacKay, Sergio Lilla, Colin Nixon, Laura C.A. Galbraith, Sonia H.Y. Kung, Elodie Renaude, Eric Hervouet, Paul Peixoto, William Clark, Ann Hedley, Giovanny Rodriguez Blanco, Chara Ntala, Linda Rushworth, Mark J. Salji, and Rafael S. Martinez
- Abstract
Significantly down-reg genes in SLFN5 KO cells and tumours
- Published
- 2023
34. Proximity Ligation in Situ Assay to Monitor Autophagy-Related Protein Interactions and Autophagy in Cancer Cells
- Author
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Paul, Peixoto, Michaël, Guittaut, and Eric, Hervouet
- Subjects
Neoplasms ,Sequestosome-1 Protein ,Autophagy ,Mitophagy ,Autophagy-Related Proteins - Abstract
Proximity ligation in situ assay (PLISA) is a powerful method to quantify endogen protein-protein interactions in cells and simultaneously identify localization of these interactions. PLISA can be used to quantify autophagy flux and can as well be adapted to assess global autophagy (SQSTM1/P62-LC3B interaction) or specific autophagy, such as mitophagy (NIX-LC3B). Here, we describe a step-by-step method to monitor autophagy using PLISA in adherent cancer cells.
- Published
- 2022
35. SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
- Author
-
Sara Zanivan, Rafael S. Martinez, William C. Clark, Paul Peixoto, Sergio Lilla, Colin Nixon, Laura C. A. Galbraith, Eric Hervouet, Ladan Fazli, Ann Hedley, Sonia H.Y. Kung, Luke Gaughan, Linda K. Rushworth, Hing Y. Leung, Martin E. Gleave, Gillian M. Mackay, Chara Ntala, Mark Salji, David Sumpton, Arnaud Blomme, Giovanny Rodriguez Blanco, and Elodie Renaude
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Proteome ,Mice, Nude ,Apoptosis ,Cell Cycle Proteins ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,urologic and male genital diseases ,Large Neutral Amino Acid-Transporter 1 ,Mice ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,In vivo ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Medicine ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,business.industry ,TOR Serine-Threonine Kinases ,ATF4 ,Transporter ,Prognosis ,medicine.disease ,Activating Transcription Factor 4 ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Androgen receptor ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Metabolome ,Cancer research ,Transcriptome ,business ,Intracellular - Abstract
Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three in vivo, androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. In vivo, SLFN5 depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC. Significance: This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer.
- Published
- 2021
36. High-Risk Mucosal Human Papillomavirus 16 (HPV16) E6 Protein and Cutaneous HPV5 and HPV8 E6 Proteins Employ Distinct Strategies To Interfere with Interferon Regulatory Factor 3-Mediated Beta Interferon Expression
- Author
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Juline Poirson, Irina Paula Suarez, Marie-Laure Straub, Alexandra Cousido-Siah, Paul Peixoto, Eric Hervouet, Anne Foster, André Mitschler, Noella Mukobo, Yassmine Chebaro, Dominique Garcin, Sevda Recberlik, Christian Gaiddon, Danièle Altschuh, Yves Nominé, Alberto Podjarny, Gilles Trave, Murielle Masson, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Equipe 2 'Réponse au Stress Cellulaire & Thérapies Innovantes' / 'Stress Response & Innovative Therapies' (STREINTH - Inserm U1113), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), and Masson, Murielle
- Subjects
Human papillomavirus 16 ,HPV ,Mucous Membrane ,[SDV]Life Sciences [q-bio] ,Immunology ,Papillomavirus Infections ,Interferon-beta ,Oncogene Proteins, Viral ,IRF3 ,Microbiology ,Virus-Cell Interactions ,three-dimensional structure ,Repressor Proteins ,interferons ,[SDV] Life Sciences [q-bio] ,interactomic ,Virology ,Insect Science ,Humans ,Interferon Regulatory Factor-3 ,Papillomaviridae ,Skin - Abstract
International audience; Persistent infection with some mucosal a-genus human papillomaviruses (HPVs; the most prevalent one being HPV16) can induce cervical carcinoma, anogenital cancers, and a subset of head and neck squamous cell carcinoma (HNSCC). Cutaneous b-genus HPVs (such as HPV5 and HPV8) associate with skin lesions that can progress into squamous cell carcinoma with sun exposure in Epidermodysplasia verruciformis patients and immunosuppressed patients. Here, we analyzed mechanisms used by E6 proteins from the aand b-genus to inhibit the interferon-b (IFNB1) response. HPV16 E6 mediates this effect by a strong direct interaction with interferon regulatory factor 3 (IRF3). The binding site of E6 was localized within a flexible linker between the DNAbinding domain and the IRF-activation domain of IRF3 containing an LxxLL motif. The crystallographic structure of the complex between HPV16 E6 and the LxxLL motif of IRF3 was solved and compared with the structure of HPV16 E6 interacting with the LxxLL motif of the ubiquitin ligase E6AP. In contrast, cutaneous HPV5 and HPV8 E6 proteins bind to the IRF3-binding domain (IBiD) of the CREB-binding protein (CBP), a key transcriptional coactivator in IRF3-mediated IFN-b expression. IMPORTANCE Persistent HPV infections can be associated with the development of several cancers. The ability to persist depends on the ability of the virus to escape the host immune system. The type I interferon (IFN) system is the first-line antiviral defense strategy. HPVs carry early proteins that can block the activation of IFN-I. Among mucosal a-genus HPV types, the HPV16 E6 protein has a remarkable property to strongly interact with the transcription factor IRF3. Instead, cutaneous HPV5 and HPV8 E6 proteins bind to the IRF3 cofactor CBP. These results highlight the versatility of E6 proteins to interact with different cellular targets. The interaction between the HPV16 E6 protein and IRF3 might contribute to the higher prevalence of HPV16 than that of other high-risk mucosal HPV types in HPV-associated cancers.
- Published
- 2022
37. The Tumor Microenvironment Impairs Th1 IFNγ Secretion through Alternative Splicing Modifications of Irf1 Pre-mRNA
- Author
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Sophie Lemoine, Christophe Hibos, Joséphine Melin, Frédérique Végran, Antoine Bernard, Sandy Chevrier, Romain Mary, Romain Boidot, Etienne Viltard, Paul Peixoto, Etienne Humblin, Fanny Chalmin, François Ghiringhelli, Mélanie Bruchard, Lionel Apetoh, Corentin Richard, Eric Hervouet, Théo Accogli, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université de Bourgogne (UB), GenomiqueENS (Genomique ENS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Thomas-Chollier, Morgane
- Subjects
0301 basic medicine ,Gene isoform ,Cancer Research ,Tumor microenvironment ,[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Chemistry ,Immunology ,Alternative splicing ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Cell biology ,03 medical and health sciences ,Splicing factor ,030104 developmental biology ,0302 clinical medicine ,Immune system ,IRF1 ,030220 oncology & carcinogenesis ,Precursor mRNA ,Transcription factor - Abstract
It is clearly established that the immune system can affect cancer response to therapy. However, the influence of the tumor microenvironment (TME) on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect the immune system. Here, we showed that the TME, via a TGFβ-dependent mechanism, increased alternative splicing events and induced the expression of an alternative isoform of the IRF1 transcription factor (IRF1Δ7) in Th1 cells. We found that the SFPQ splicing factor (splicing factor, proline- and glutamine-rich) was responsible for the IRF1Δ7 production. We also showed, in both mice and humans, that the IRF1 alternative isoform altered the full-length IRF1 transcriptional activity on the Il12rb1 promoter, resulting in decreased IFNγ secretion in Th1 cells. Thus, the IRF1Δ7 isoform was increased in the TME, and inhibiting IRF1Δ7 expression could potentiate Th1 antitumor responses.
- Published
- 2021
38. Autophagy is associated with a robust specific transcriptional signature in breast cancer subtypes
- Author
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Perez Valérie, Jean Paul Feugeas, Paul Peixoto, Franck Monnien, Guittaut Michaël, Céline Grandvallet, Eric Hervouet, and Gilles Despouy
- Subjects
0301 basic medicine ,Cancer Research ,autophagy ,Autophagy ,ATG5 ,Cancer ,BECN1 ,Biology ,medicine.disease ,Phenotype ,Transcriptome ,gene expression signature ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,breast cancer ,030220 oncology & carcinogenesis ,Gene expression ,Genetics ,Cancer research ,medicine ,transcriptome ,Research Paper - Abstract
Previous works have described that autophagy could be associated to both pro- and anti-cancer properties according to numerous factors, such as the gene considered, the step of autophagy involved or the cancer model used. These data might be explained by the fact that some autophagy-related genes may be involved in other cellular processes and therefore differently regulated according to the type or the grade of the tumor. Indeed, using different approaches of transcriptome analysis in breast cancers, and further confirmation using digital PCR, we identified a specific signature of autophagy gene expression associated to Luminal A or Triple Negative Breast Cancers (TNBC). Moreover, we confirmed that ATG5, an autophagy gene specifically expressed in TNBC, favored cell migration, whereas BECN1, an autophagy gene specifically associated with ER-positive breast cancers, induced opposite effects. We also showed that overall inhibition of autophagy promoted cell migration suggesting that the role of individual ATG genes in cancer phenotypes was not strictly dependent of their function during autophagy. Finally, our work led to the identification of TXNIP1 as a potential biomarker associated to autophagy induction in breast cancers. This gene could become an essential tool to quantify autophagy levels in fixed biopsies, sort tumors according to their autophagy levels and determine the best therapeutic treatment.
- Published
- 2020
39. Proximity Ligation in Situ Assay to Monitor Autophagy-Related Protein Interactions and Autophagy in Cancer Cells
- Author
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Paul Peixoto, Michaël Guittaut, and Eric Hervouet
- Published
- 2022
40. Droplet digital PCR allows vector copy number assessment and monitoring of experimental CAR T cells in murine xenograft models or approved CD19 CAR T cell-treated patients
- Author
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Rim Trad, Rafik Haderbache, Pauline Varlet, Paul-Oliver Rouzaire, Catherine Thieblemeont, Christophe Ferrand, Ibrahim Yakoub Agha, Emmanuel Bachy, Sophie Caillat-Zucman, Eric Hervouet, Vincent Allain, Pierre Sujobert, Clementine Nicod, Fabienne Venet, Denis Caillot, Mathieu Neto Da Rocha, Xavier Roussel, Walid Warda, Lucie Bouquet, Jean Christophe Bories, Olivier Casasnovas, Nicolas Boissel, Melanie Guiot, Marina Deschamps, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), and Université Clermont Auvergne (UCA)
- Subjects
DNA Copy Number Variations ,Monitoring ,T-Lymphocytes ,Tisa-cel ,Antigens, CD19 ,IL-1RAP ,Immunotherapy, Adoptive ,Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,CD19 ,Flow cytometry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Multiplicity of infection ,medicine ,Animals ,Humans ,Chimeric antigen receptor ,B cell ,030304 developmental biology ,0303 health sciences ,biology ,medicine.diagnostic_test ,business.industry ,Methodology ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,General Medicine ,medicine.disease ,Axi-cel ,3. Good health ,medicine.anatomical_structure ,Droplet digital PCR ,030220 oncology & carcinogenesis ,NSG mouse ,Cancer research ,biology.protein ,Medicine ,Heterografts ,Bone marrow ,Lymphoma, Large B-Cell, Diffuse ,business ,Diffuse large B-cell lymphoma - Abstract
Background Genetically engineered chimeric antigen receptor (CAR) T lymphocytes are promising therapeutic tools for cancer. Four CAR T cell drugs, including tisagenlecleucel (tisa-cel) and axicabtagene-ciloleucel (axi-cel), all targeting CD19, are currently approved for treating B cell malignancies. Flow cytometry (FC) remains the standard for monitoring CAR T cells using a recombinant biotinylated target protein. Nevertheless, there is a need for additional tools, and the challenge is to develop an easy, relevant, highly sensitive, reproducible, and inexpensive detection method. Molecular tools can meet this need to specifically monitor long-term persistent CAR T cells. Methods Based on 2 experimental CAR T cell constructs, IL-1RAP and CS1, we designed 2 quantitative digital droplet (ddPCR) PCR assays. By targeting the 4.1BB/CD3z (28BBz) or 28/CD3z (28z) junction area, we demonstrated that PCR assays can be applied to approved CD19 CAR T drugs. Both 28z and 28BBz ddPCR assays allow determination of the average vector copy number (VCN) per cell. We confirmed that the VCN is dependent on the multiplicity of infection and verified that the VCN of our experimental or GMP-like IL-1RAP CAR T cells met the requirement ( Results 28BBz and 28z ddPCR assays applied to 2 tumoral (acute myeloid leukemia (AML) or multiple myeloma (MM) xenograft humanized NSG mouse models allowed us to quantify the early expansion (up to day 30) of CAR T cells after injection. Interestingly, following initial expansion, when circulating CAR T cells were challenged with the tumor, we noted a second expansion phase. Investigation of the bone marrow, spleen and lung showed that CAR T cells disseminated more within these tissues in mice previously injected with leukemic cell lines. Finally, circulating CAR T cell ddPCR monitoring of R/R acute lymphoid leukemia or diffuse large B cell lymphoma (n = 10 for tisa-cel and n = 7 for axi-cel) patients treated with both approved CAR T cells allowed detection of early expansion, which was highly correlated with FC, as well as long-term persistence (up to 450 days), while FC failed to detect these events. Conclusion Overall, we designed and validated 2 ddPCR assays allowing routine or preclinical monitoring of early- and long-term circulating approved or experimental CAR T cells, including our own IL-1RAP CAR T cells, which will be evaluated in an upcoming phase I clinical trial.
- Published
- 2021
41. DHX15-independent roles for TFIP11 in U6 snRNA modification, U4/U6.U5 tri-snRNP assembly and pre-mRNA splicing fidelity
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Marc Thiry, Eric A. Perpète, Eric Hervouet, Denis L. J. Lafontaine, Franck Dequiedt, Agnès Méreau, Amandine Duchemin, Catherine Michaux, Paul Peixoto, Denis Mottet, Ludivine Wacheul, Yann Audic, Tina O'Grady, Felix G.M. Ernst, Sarah Hanache, GIGA [Université Liège], Université de Liège, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université libre de Bruxelles (ULB), Université de Namur [Namur] (UNamur), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), This work was supported by grants from the FNRS–Belgium (CDR Grant No. J003618F), TELEVIE, Fonds Léon Frédéricq and Fonds Spéciaux de la Recherche de l’Université de Liège (ULiege). A.D. is FNRS-FRIA fellow. T.O’G. is FNRS Postdoctoral Researcher. S.H. is FNRS-TELEVIE fellow. E.P. and D.L.J.L. are FNRS Senior Research Associates. C.M. and D.M. are FNRS Research Associates., Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC)
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Spliceosome ,Cell Survival ,Ribonucleoprotein, U4-U6 Small Nuclear ,Science ,RNA Splicing ,General Physics and Astronomy ,Mitosis ,Coiled Bodies ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,environment and public health ,Methylation ,General Biochemistry, Genetics and Molecular Biology ,Article ,Non-coding RNAs ,03 medical and health sciences ,0302 clinical medicine ,RNA, Small Nuclear ,RNA Precursors ,Humans ,Nuclear Speckles ,RNA, Small Nucleolar ,snRNP ,Small nucleolar RNA ,Ribonucleoprotein, U5 Small Nuclear ,030304 developmental biology ,SnRNA modification ,Fibrillarin ,RNA metabolism ,0303 health sciences ,Multidisciplinary ,Chemistry ,Protein Stability ,urogenital system ,Nuclear Proteins ,General Chemistry ,3. Good health ,Cell biology ,Cajal body ,RNA splicing ,Spliceosomes ,RNA ,RNA Splicing Factors ,030217 neurology & neurosurgery ,Small nuclear RNA ,Cell Nucleolus ,HeLa Cells ,Protein Binding - Abstract
The U6 snRNA, the core catalytic component of the spliceosome, is extensively modified post-transcriptionally, with 2’-O-methylation being most common. However, how U6 2’-O-methylation is regulated remains largely unknown. Here we report that TFIP11, the human homolog of the yeast spliceosome disassembly factor Ntr1, localizes to nucleoli and Cajal Bodies and is essential for the 2’-O-methylation of U6. Mechanistically, we demonstrate that TFIP11 knockdown reduces the association of U6 snRNA with fibrillarin and associated snoRNAs, therefore altering U6 2′-O-methylation. We show U6 snRNA hypomethylation is associated with changes in assembly of the U4/U6.U5 tri-snRNP leading to defects in spliceosome assembly and alterations in splicing fidelity. Strikingly, this function of TFIP11 is independent of the RNA helicase DHX15, its known partner in yeast. In sum, our study demonstrates an unrecognized function for TFIP11 in U6 snRNP modification and U4/U6.U5 tri-snRNP assembly, identifying TFIP11 as a critical spliceosome assembly regulator., In yeast, TFIP11 and DHX15 promote the disassembly of spliceosome complex after splicing is completed. Here the authors show that human TFIP11 functions independently of DHX15 and is required for U6 snRNA 2’-O-methylation and U4/U6.U5 tri-snRNP assembly.
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- 2021
42. The detection of specific hypermethylated WIF1 and NPY genes in circulating DNA by crystal digital PCR™ is a powerful new tool for colorectal cancer diagnosis and screening
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Zohair Selmani, Alexis Overs, Borg Christophe, Jean-Luc Prétet, Mylène Flammang, Eric Hervouet, Laurent Bermont, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), and Malbec, Odile
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Male ,Cancer Research ,Colorectal cancer ,[SDV]Life Sciences [q-bio] ,medicine.disease_cause ,Polymerase Chain Reaction ,Circulating Tumor DNA ,0302 clinical medicine ,Surgical oncology ,Neuropeptide Y ,Digital polymerase chain reaction ,RC254-282 ,Aged, 80 and over ,0303 health sciences ,DNA methylation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Middle Aged ,3. Good health ,[SDV] Life Sciences [q-bio] ,Oncology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,Epigenetics ,Colorectal Neoplasms ,Adult ,Genetic Markers ,Context (language use) ,NPY ,Sensitivity and Specificity ,03 medical and health sciences ,Confidence Intervals ,Genetics ,medicine ,Humans ,Liquid biopsy ,Adaptor Proteins, Signal Transducing ,Aged ,030304 developmental biology ,business.industry ,Research ,medicine.disease ,Cancer research ,Carcinogenesis ,business ,WIF1 ,Digital PCR - Abstract
Background In oncology, liquid biopsy is of major relevance from theranostic point of view. The searching for mutations in circulating tumor DNA (ctDNA) in case of colorectal cancers (CRCs) allows the optimization of patient care. In this context, independent of mutation status biomarkers are required for its detection to confirm the presence of ctDNA in liquid biopsies. Indeed, the hypermethylation of NPY and WIF1 genes appear to be an ideal biomarker for the specific detection of ctDNA in CRCs. The objective of this work is to develop the research of hypermethylation of NPY and WIF1 by Crystal Digital PCR™ for the detection of ctDNA in CRCs. Methods Detection of hypermethylated NPY and WIF1 was developed on Cristal digital PCR™. Biological validation was performed from a local cohort of 22 liquid biopsies and 23 tissue samples from patients with CRC. These patients were treated at the University Hospital of Besancon (France). Results The local cohort study confirmed that NPY and WIF1 were significantly hypermethylated in tumor tissues compared to adjacent non-tumor tissues (WIF1 p NPY p NPY or WIF1 in liquid biopsy had a 95.5% [95%CI 77–100%] sensitivity and 100% [95%CI 69–100%] specificity. Conclusion Using Crystal digital PCR™, this study shows that hypermethylation of NPY and WIF1 are constant specific biomarkers of CRCs regardless of a potential role in carcinogenesis.
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- 2021
43. The NMD Pathway Regulates GABARAPL1 mRNA during the EMT
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Alexis Overs, Annick Fraichard, Michael Herfs, Stefania Millevoi, Michaël Guittaut, Timothée Baudu, Paul Peixoto, Valérie Perez, Anne Peigney, Eric Hervouet, Marie Ancion, Aurélie Baguet, and Chloé Parratte
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A549 cell ,autophagy ,QH301-705.5 ,GABARAP ,ATG8 ,Autophagy ,Medicine (miscellaneous) ,EIF4A3 ,Biology ,Phenotype ,General Biochemistry, Genetics and Molecular Biology ,lung cancer ,Gene expression ,Cancer research ,NMD ,LC3 ,Biology (General) ,Reprogramming ,GABARAPL1 - Abstract
EMT is a reversible cellular process that is linked to gene expression reprogramming, which allows for epithelial cells to undergo a phenotypic switch to acquire mesenchymal properties. EMT is associated with cancer progression and cancer therapeutic resistance and it is known that, during the EMT, many stress response pathways, such as autophagy and NMD, are dysregulated. Therefore, our goal was to study the regulation of ATG8 family members (GABARAP, GABARAPL1, LC3B) by the NMD and to identify molecular links between these two cellular processes that are involved in tumor development and metastasis formation. IHC experiments, which were conducted in a cohort of patients presenting lung adenocarcinomas, showed high GABARAPL1 and low UPF1 levels in EMT+ tumors. We observed increased levels of GABARAPL1 correlated with decreased levels of NMD factors in A549 cells in vitro. We then confirmed that GABARAPL1 mRNA was indeed targeted by the NMD in a 3′UTR-dependent manner and we identified four overlapping binding sites for UPF1 and eIF4A3 that are potentially involved in the recognition of this transcript by the NMD pathway. Our study suggests that 3′UTR-dependent NMD might be an important mechanism that is involved in the induction of autophagy and could represent a promising target in the development of new anti-cancer therapies.
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- 2021
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44. From 1957 to Nowadays: A Brief History of Epigenetics
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Eric Hervouet, Paul Peixoto, Aurélien A. Sérandour, Pierre-François Cartron, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), EPIgenetics and GENe EXPression Technical Plateform (EPIGENExp), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Apoptose et progression tumorale (ICO, Saint-Herblain), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], EpiSAVMEN Network (Région Pays de la Loire) [Saint-Herblain], LabEX IGO Immunothérapie Grand Ouest, École Centrale de Nantes (ECN), DImaCell Platform, Université Bourgogne Franche-Comté [COMUE] (UBFC), Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Dispositif Inter-régional d'Imagerie Cellulaire [Dijon] (DImaCell), Procédés Alimentaires et Microbiologiques (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ingénierie et biologie cellulaire et tissulaire (IBCT (ex IFR133)), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Agroécologie [Dijon], and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
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Epigenomics ,History ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Review ,History, 21st Century ,Catalysis ,Epigenesis, Genetic ,Inorganic Chemistry ,lcsh:Chemistry ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Epitranscriptomics ,histones ,Animals ,Humans ,Epigenetics ,Physical and Theoretical Chemistry ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,030304 developmental biology ,Cognitive science ,0303 health sciences ,DNA methylation ,epigenetics ,Organic Chemistry ,General Medicine ,History, 20th Century ,Computer Science Applications ,lcsh:Biology (General) ,lcsh:QD1-999 ,030220 oncology & carcinogenesis ,Identification (biology) ,history ,epitranscriptomics ,Protein Processing, Post-Translational - Abstract
International audience; Due to the spectacular number of studies focusing on epigenetics in the last few decades, and particularly for the last few years, the availability of a chronology of epigenetics appears essential. Indeed, our review places epigenetic events and the identification of the main epigenetic writers, readers and erasers on a historic scale. This review helps to understand the increasing knowledge in molecular and cellular biology, the development of new biochemical techniques and advances in epigenetics and, more importantly, the roles played by epigenetics in many physiological and pathological situations.
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- 2020
45. Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer
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Rafael S. Martinez, Mark J. Salji, Linda Rushworth, Chara Ntala, Giovanny Rodriguez Blanco, Ann Hedley, William Clark, Paul Peixoto, Eric Hervouet, Elodie Renaude, Sonia H.Y. Kung, Laura C.A. Galbraith, Colin Nixon, Sergio Lilla, Gillian M. MacKay, Ladan Fazli, David Sumpton, Martin E. Gleave, Sara Zanivan, Arnaud Blomme, and Hing Y. Leung
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urologic and male genital diseases - Abstract
Androgen-deprivation therapy (ADT) is the standard of care for the treatment of non-resectable prostate cancer (PCa). Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we perform a comparative proteomic analysis of three in vivo, androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome. In vivo, SLFN5 depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.
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- 2020
46. 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer
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Duncan Graham, Paul Peixoto, Mélanie Planque, Mark Salji, Karen Faulds, Hing Y. Leung, Ernest Mui, Catriona A. Ford, David Sumpton, Giovanny Rodriguez Blanco, Colin Nixon, Luke Gaughan, Sara Zanivan, Chara Ntala, Sergio Lilla, Elke Markert, Gillian M. Mackay, Rachana Patel, Jurre J. Kamphorst, Peter Repiscak, Arnaud Blomme, Grace McGregor, Lauren E. Jamieson, Sarah-Maria Fendt, Eric Hervouet, Cancer Research UK Beatson Institute [Glasgow], University of Glasgow, University of Strathclyde [Glasgow], Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), EPIgenetics and GENe EXPression Technical Plateform (EPIGENExp), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Dispositif Inter-régional d'Imagerie Cellulaire [Dijon] (DImaCell), Procédés Alimentaires et Microbiologiques (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ingénierie et biologie cellulaire et tissulaire (IBCT (ex IFR133)), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Newcastle University [Newcastle], This work was supported by Cancer Research UK Beatson Institute core funding (C596/A17196) and CRUK core group awarded to HYL (A15151) and to SZ (A12935). P.P. and E.H. were funded by grants from 'La ligue Contre le Cancer', 'la région Bourgogne Franche-Comté' and 'Canceropole Grand Est'. M.S. is a Medical Research Council Clinical Research Fellow (MR/L017997/1). C.N. is the recipient of CRUK Clinical Research Fellowship (grant 300444-01). D.G. and K.F. acknowledge support from the EPSRC grant EP/L014165/1 that supported L.J. S.-M.F. acknowledges FWO funding and KU Leuven Methusalem co-funding., Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Agroécologie [Dijon], and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
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Male ,Proteomics ,0301 basic medicine ,General Physics and Astronomy ,Reductase ,urologic and male genital diseases ,Prostate cancer ,0302 clinical medicine ,Homeostasis ,QD ,lcsh:Science ,Phospholipids ,Multidisciplinary ,Chemistry ,Prostate ,Cancer metabolism ,Phenotype ,Mitochondria ,3. Good health ,Prostatic Neoplasms, Castration-Resistant ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Disease Progression ,Oxidoreductases Acting on CH-CH Group Donors ,Science ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,RC0254 ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,LNCaP ,Androgen Receptor Antagonists ,medicine ,Humans ,Metabolomics ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Lipid metabolism ,General Chemistry ,Lipid Metabolism ,medicine.disease ,Androgen receptor ,030104 developmental biology ,Lipidomics ,Unfolded protein response ,Cancer research ,lcsh:Q - Abstract
Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineate a subset of proteins consistently associated with ARI resistance and highlight mitochondrial 2,4-dienoyl-CoA reductase (DECR1), an auxiliary enzyme of beta-oxidation, as a clinically relevant biomarker for CRPC. Mechanistically, DECR1 participates in redox homeostasis by controlling the balance between saturated and unsaturated phospholipids. DECR1 knockout induces ER stress and sensitises CRPC cells to ferroptosis. In vivo, DECR1 deletion impairs lipid metabolism and reduces CRPC tumour growth, emphasizing the importance of DECR1 in the development of treatment resistance., Androgen receptor (AR) signalling regulates cellular metabolism in prostate cancer. Here, the authors perform a proteomics and metabolomics characterisation of prostate cancer cells adapted to long-term resistance to AR inhibition and show rewiring of glucose and lipid metabolism, and further identify a signature associated with resistance to AR inhibition.
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- 2020
47. GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback
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Annick Fraichard, Marine Jacquet, Michael Herfs, Celia Reynders, Marie Ancion, Chloé Parratte, Timothée Baudu, Jean-Paul Feugeas, Eric Hervouet, Marc Vigneron, Aurélie Baguet, Gilles Despouy, Michaël Guittaut, and Valérie Perez
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autophagy ,General Immunology and Microbiology ,QH301-705.5 ,ATG8 ,Autophagy ,GABARAPL1 ,EMT ,SMAD ,Biology ,medicine.disease ,Article ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,embryonic structures ,medicine ,Cancer research ,cancer ,Adenocarcinoma ,Biology (General) ,Signal transduction ,General Agricultural and Biological Sciences ,Transcription factor ,Intracellular - Abstract
Simple Summary Epithelial–mesenchymal transition (EMT) is involved in metastasis formation, chemoresistance, apoptosis resistance, and acquisition of stem cell properties, making this process an attractive target in cancer. However, direct targeting of EMT remains challenging. Autophagy—an intracellular mechanism—has been noted to be involved in the regulation of EMT—mainly by its involvement in the degradation of EMT actors, explaining why understanding of how autophagy could regulate EMT might be promising in the development of new cancer therapies. Here, we found that GABARAPL1—an autophagy-related gene—was increased in human NSCLC mesenchymal tumors compared to epithelial tumors, and induction of EMT in an A549 lung cancer cell line by TGF-β/TNF-α cytokines also led to an increase in GABARAPL1 expression. This regulation could involve the EMT-related transcription factors of the SMAD family. To understand the role of GABARAPL1 in EMT regulation in lung cancer cells, A549 KO GABARAPL1 were designed and used to investigate whether GABARAPL1 could inhibit EMT via its involvement in SMAD degradation. The results indicate that GABARAPL1-mediated autophagic degradation could intervene as a negative EMT-regulatory loop. Abstract The pathway of selective autophagy, leading to a targeted elimination of specific intracellular components, is mediated by the ATG8 proteins, and has been previously suggested to be involved in the regulation of the Epithelial–mesenchymal transition (EMT) during cancer’s etiology. However, the molecular factors and steps of selective autophagy occurring during EMT remain unclear. We therefore analyzed a cohort of lung adenocarcinoma tumors using transcriptome analysis and immunohistochemistry, and found that the expression of ATG8 genes is correlated with that of EMT-related genes, and that GABARAPL1 protein levels are increased in EMT+ tumors compared to EMT- ones. Similarly, the induction of EMT in the A549 lung adenocarcinoma cell line using TGF-β/TNF-α led to a high increase in GABARAPL1 expression mediated by the EMT-related transcription factors of the SMAD family, whereas the other ATG8 genes were less modified. To determine the role of GABARAPL1 during EMT, we used the CRISPR/Cas9 technology in A549 and ACHN kidney adenocarcinoma cell lines to deplete GABARAPL1. We then observed that GABARAPL1 knockout induced EMT linked to a defect of GABARAPL1-mediated degradation of the SMAD proteins. These findings suggest that, during EMT, GABARAPL1 might intervene in an EMT-regulatory loop. Indeed, induction of EMT led to an increase in GABARAPL1 levels through the activation of the SMAD signaling pathway, and then GABARAPL1 induced the autophagy-selective degradation of SMAD proteins, leading to EMT inhibition.
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- 2021
48. Abstract P1-06-09: Relationships between breast cancer subtypes and expression of autophagy related genes
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J-P Feugeas, M Boyer-Guittaut, S Belmiloudi, Eric Hervouet, and Paul Peixoto
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Oncology ,Cancer Research ,medicine.medical_specialty ,ATG5 ,Cancer ,Estrogen receptor ,BECN1 ,Biology ,medicine.disease ,medicine.disease_cause ,Transcriptome ,Internal medicine ,Cancer cell ,medicine ,Cancer research ,skin and connective tissue diseases ,Carcinogenesis ,MAP1LC3B - Abstract
Background: Breast cancer (BC) is a heterogeneous disease and can be classified according to the expression of four genes: estrogen receptor (ER), progesterone receptor (PGR), human epidermal growth factor receptor 2 (HER2) and marker of proliferation KI67. Four groups of BC have been described: Luminal A (ER+ or PGR+, KI67- HER2-), Luminal B (ER+ or PGR+, KI67+ or HER2+), HER2 (ER- HER2+) and triple negative (ER- PGR- HER2-). Autophagy is a lysosomal degradation pathway which plays a crucial dual role in tumorigenesis, producing pro-survival or pro-death activity. Altered autophagy has been observed in BC but no study has described transcript level variations of "autophagy genes" according to sub-groups. In order to further explore those alterations, we analyzed gene expression of 40 "autophagy genes" in normal and tumor cells using public transcriptomic data. Samples and Methods: 5497 transcriptomes were obtained from raw data downloaded from public databases. Two distinct Affymetrix series were built after GC-RMA normalization: one from HG-U133A arrays (n=2806) and one from HG-U133 plus2 arrays (n=2691). Each series was standardized with the Aroma R package that was designed to normalize multicenter extremely large Affymetrix data sets. The same computations were performed in the two data set in order to cross-validate the results. Samples were classified with a reduced number of genes (such as for St Gallen classification) and with classifiers using 50 or more than 300 genes (PAM50, CIT and IntClust centroids). Results: In each of the two series, there were about 500 Basal, 300 HER2, 1800 Luminal tumors and 100 normal epithelial breast cells. Positivity or negativity of four genes (ER, PGR, KI67, HER2) produced robust classifications concordant with PAM50 classification based upon centroids. Within the 40 "autophagy genes" studied, at least 10 genes were significantly correlated with one or two sub-groups: ATG3 and ATG9A were associated with ER- tumors including basal group; ATG2B , BECN1 and ULK2 were positively correlated with ER expression and luminal subtypes; ULK1 and RAB24 were associated with ER+HER2+ tumors and MAP1LC3B and ATG5 with ER-HER2+ subgroup; GABARAPL1 was more expressed in normal breast tissue than in cancer cells. Discussion: Exploring autophagy in large-scale transcriptome data, we confirmed a previous result showing that GABARAPL1 expression is reduced in breast cancer cells compared with the normal epithelial cells. Interestingly, transcript levels of "autophagy genes"were not evenly distributed among the different tumor subtypes. For instance, some genes were preferentially expressed in ER+ subtypes and others in ER- tumors, suggesting that autophagy might play different roles in the different subgroups, providing different potential targets for therapy. Citation Format: Feugeas J-P, Belmiloudi S, Boyer-Guittaut M, Peixoto P, Hervouet E. Relationships between breast cancer subtypes and expression of autophagy related genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-06-09.
- Published
- 2017
49. The Tumor Microenvironment Impairs Th1 IFNγ Secretion through Alternative Splicing Modifications of
- Author
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Antoine, Bernard, Christophe, Hibos, Corentin, Richard, Etienne, Viltard, Sandy, Chevrier, Sophie, Lemoine, Joséphine, Melin, Etienne, Humblin, Romain, Mary, Théo, Accogli, Fanny, Chalmin, Mélanie, Bruchard, Paul, Peixoto, Eric, Hervouet, Lionel, Apetoh, François, Ghiringhelli, Frédérique, Végran, and Romain, Boidot
- Subjects
Receptors, Interleukin-12 ,Th1 Cells ,Gene Expression Regulation, Neoplastic ,Alternative Splicing ,Disease Models, Animal ,Interferon-gamma ,Mice ,Cell Line, Tumor ,Gene Knockdown Techniques ,Neoplasms ,RNA Precursors ,Tumor Microenvironment ,Animals ,Humans ,Protein Isoforms ,Tumor Escape ,RNA, Messenger ,RNA-Seq ,Promoter Regions, Genetic ,Interferon Regulatory Factor-1 - Abstract
It is clearly established that the immune system can affect cancer response to therapy. However, the influence of the tumor microenvironment (TME) on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect the immune system. Here, we showed that the TME, via a TGFβ-dependent mechanism, increased alternative splicing events and induced the expression of an alternative isoform of the IRF1 transcription factor (IRF1Δ7) in Th1 cells. We found that the SFPQ splicing factor (splicing factor, proline- and glutamine-rich) was responsible for the IRF1Δ7 production. We also showed, in both mice and humans, that the IRF1 alternative isoform altered the full-length IRF1 transcriptional activity on the
- Published
- 2019
50. Mitochondrial Dysfunction, Immune Systems, Their Diseases, and Possible Treatments
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Michaël Boyer-Guittaut, Eric Hervouet, and Elise Jacquin
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Immune system ,Immunology ,Biology - Published
- 2019
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