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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high-risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC-related genetic and molecular aberrations, enhancing the accuracy of prognostic evaluations compared to conventional MYC biomarkers. Our results indicate that MYCSS significantly refines prognostic accuracy beyond that of conventional MYC biomarkers focused on genetic aberrations. More importantly, we found that nearly 50% of patients identified as high risk by traditional MYC metrics actually share similar survival prospects with those having no MYC aberrations. These patients may benefit from standard GCB-based therapies rather than more aggressive treatments. MYCSS provides a robust signature that identifies high-risk patients, aiding in the precision treatment of DLBCL, and minimizing the potential for overtreatment., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: Fluorescence in situ hybridization (FISH) using break-apart probes is recommended for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). Unbalanced MYC break-apart patterns, in which the red or green signal is lost, are commonly reported as an equivocal result by clinical laboratories. In a cohort of 297 HGBCL-DH-BCL2, 13% of tumors had unbalanced MYC break-apart patterns with loss of red (LR; 2%) or loss of green (LG; 11%) signal. To determine the significance of these patterns, MYC rearrangements were characterized by sequencing in 130 HGBCL-DH-BCL2, including 3 LR and 14 LG tumors. A MYC rearrangement was identified for 71% of tumors with LR or LG patterns, with the majority involving immunoglobulin loci or other recurrent MYC rearrangement partners. The architecture of these rearrangements consistently preserved the rearranged MYC allele, with the MYC gene predicted to be on the derivative chromosome containing the signal that is still present in nearly all cases. MYC protein expression, MYC messenger RNA expression, and the proportion of tumors expressing the dark-zone signature was not significantly different between balanced and unbalanced groups. These results support a recommendation that unbalanced MYC break-apart FISH patterns be reported as positive for MYC rearrangement in the context of diagnosing HGBCL-DH-BCL2., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: The purpose of this work was to evaluate c-MYC gene amplification in the substrate of prostate acinar adenocarcinoma at various Gleason scores and various stages of the disease, taking into account the morphological characteristics of the tumor., Material and Methods: The number of cases in the study was 82, including the control group - 12 cases. Morphological assessment included: determination of the total Gleason score, grading group, assessment of lymphovascular/perineural invasion, and architectural characteristics of the tumor. Gene amplification was assessed by FISH using the c-MYC (8q24)/SE8 probe., Results: In all cases of the study group, amplification of the c-MYC gene was detected in the tumor, with a significant difference from the control group ( p <0.05). When assessing cases with 4-6 fold copies of the gene, significant differences were established between patients with stages II and III of the disease and stage IV (10.0 and 13.5 versus 30.0) ( p <0.05). Cluster amplification of the c-MYC gene was detected with equal frequency in groups of patients with stages III and IV of the disease, while in stage II of the disease, the event almost did not occur ( p <0.05). A significant increase in the level of c-MYC gene amplification was found in groups with advanced stages of the disease ( p <0.02). Non-cluster amplification significantly distinguishes T4M0 and T4M1 stage patients from the rest with a significant increase in the score ( p <0.05). In the metastatic stage of the disease, there was an increase c-MYC gene amplification compared to the non-metastatic stage ( p <0.02). The copy number of the c-MYC gene was significantly higher in cases with perineural and lymphovascular invasion, as well as in cases of cribriform tumor organization ( p <0.05)., Conclusion: Amplification of the c-MYC gene in prostate tumor cells is associated with advanced stages of the disease (T4M0 and T4M1) with an increase in the copy number of the gene during the metastatic stage of the process. It was found that increased amplification of the c-MYC gene distinguishes groups of patients whose tumors exhibit perineural and lymphovascular invasion, as well as a cribriform pattern of tumor organization.

G-quadruplex (G4) structures play integral roles in modulating biological functions and can be regulated by small molecules. The MYC gene is critical during tumor initiation and malignant progression, in which G4 acts as an important modulation motif. Herein, we reported the MYC promoter G4 recognized by a platinum(II) compound Pt-phen. Two Pt-phen-MYC G4 complex structures in 5 mM K+ were determined by NMR. The Pt-phen first strongly binds the 3'-end of MYC G4 to form a 1:1 3'-end binding complex and then binds 5'-end to form a 2:1 complex with more Pt-phen. In the complexes, the Pt-phen molecules are well-defined and stack over four bases at the G-tetrad for a highly extensive π-π interaction, with the Pt atom aligning with the center of the G-tetrad. The flanking residues were observed to rearrange and cover on top of Pt-phen to stabilize the whole complex. We further demonstrated that Pt-phen targets G4 DNA in living cells and represses MYC gene expression in cancer cells. Our work elucidated the structural basis of ligand binding to MYC promoter G4. The platinum compound bound G4 includes multiple complexes formation, providing insights into the design of metal ligands targeting oncogene G4 DNA., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Regular exercise is believed to suppress cancer progression. However, the precise molecular mechanisms by which exercise prevents cancer development remain unclear. In this study, using a steatosis-associated liver cancer mouse model, we found that regular exercise at a speed of 18 m/min for 20 min daily suppressed liver cancer development. To explore the underlying mechanisms, we examined the gene expression profiles in the livers of the exercise and non-exercise groups. The expressions of circadian genes, such as Per1 and Cry2, were upregulated in the exercise group. As circadian rhythm disruption is known to cause various diseases, including cancer, improving circadian rhythm through exercise could contribute to cancer prevention. We further found that the expression of a series of E2F1 and c-Myc target genes that directly affect the proliferation of cancer cells was downregulated in the exercise group. However, the expression of E2F1 and c-Myc was transcriptionally unchanged but degraded at the post-translational level by exercise. Cry2, which is regulated by the Skp1-Cul1-FBXL3 (SCF FBXL3 ) ubiquitin ligase complex by binding to FBXL3, can form a complex with E2F1 and c-Myc, which we think is the mechanism to degrade them. Our study revealed a previously unknown mechanism by which exercise prevents cancer development., (© 2024 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Erythropoiesis is a multistep process of erythroid cell production that is controlled by multiple regulatory factors. Ribosome rescue factor PELO plays a crucial role in cell meiotic division and mice embryonic development. However, the function of PELO in erythroid differentiation remains unclear. Here, we showed that knockdown of PELO increased hemin-induced erythroid differentiation of K562 and HEL cells, exhibiting a higher number of benzidine-positive cells and increased mRNA levels of erythroid genes. PELO knockdown inhibited the proliferation and cell cycle progression and promoted apoptosis of K562 cells. Mechanistically, PELO could regulate the expression of KLF10 through interaction with MYC. Moreover, KLF10 knockdown also enhanced erythroid differentiation of K562 and HEL cells induced by hemin. Collectively, our results demonstrated that PELO regulates erythroid differentiation and increases KLF10 expression levels by interacting with MYC., (© 2024 Federation of European Biochemical Societies.)

MYC has been identified to profoundly influence a wide range of pathologic processes in cancers. However, the prognostic value of MYC-related genes in pancreatic adenocarcinoma (PAAD) remains unclarified. Gene expression data and clinical information of PAAD patients were obtained from The Cancer Genome Atlas (TCGA) database (training set). Validation sets included GSE57495, GSE62452, and ICGC-PACA databases. LASSO regression analysis was used to develop a risk signature for survival prediction. Single-cell sequencing data from GSE154778 and CRA001160 datasets were analyzed. Functional studies were conducted using siRNA targeting RHOF and ITGB6 in PANC-1 cells. High MYC expression was found to be significantly associated with a poor prognosis in patients with PAAD. Additionally, we identified seven genes (ADGRG6, LINC00941, RHOF, SERPINB5, INSYN2B, ITGB6, and DEPDC1) that exhibited a strong correlation with both MYC expression and patient survival. They were then utilized to establish a risk model (MYCsig), which showed robust predictive ability. Furthermore, MYCsig demonstrated a positive correlation with the expression of HLA genes and immune checkpoints, as well as the chemotherapy response of PAAD. RHOF and ITGB6, expressed mainly in malignant cells, were identified as key oncogenes regulating chemosensitivity through EMT. Downregulation of RHOF and ITGB6 reduced cell proliferation and invasion in PANC-1 cells. The developed MYCsig demonstrates its potential in enhancing the management of patients with PAAD by facilitating risk assessment and predicting response to adjuvant chemotherapy. Additionally, our study identifies RHOF and ITGB6 as novel oncogenes linked to EMT and chemoresistance in PAAD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hyperproliferation driven by the protooncogene MYC may lead to tumor suppressor p53 activating DNA damage that has been presumed to derive from hypertranscription and over-replication. Here, we report that excessive MYC-topoisome (MYC/topoisomerase 1/topoisomerase 2) activity acutely damages DNA-activating pATM and p53. In turn, MYC is shut off and degraded, releasing TOP1 and TOP2A from MYC topoisomes in vitro and in vivo. To manage the topological and torsional stress generated at its target genes, p53 assembles a separate topoisome. Because topoisomerase activity is intrinsically DNA damaging, p53 topoisomes provoke an initial burst of DNA damage. Because p53, unlike MYC, upregulates the DNA-damage response (DDR) and activates tyrosyl-DNA-phosphodiesterase (TDP) 1 and TDP2, it suppresses further topoisome-mediated damage. The physical coupling and activation of TOP1 and TOP2 by p53 creates a tool that supports p53-target expression while braking MYC-driven proliferation in mammalian cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The authors declare that all methods were performed in accordance with the relevant guidelines and regulations. The procedures for collecting human blood samples were approved by the Institutional Review Board of the National Taiwan University Hospital. Signed informed consent was obtained from all participants. Additionally, the authors have obtained written informed consent for publication of the images., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The MYC oncogene is frequently overexpressed in tumors and inhibition of its translation is considered an attractive therapeutic opportunity. Despite numerous reports proposing an internal ribosome entry site (IRES) within the MYC Upstream Region (MYC UR) to sustain MYC translation during cellular stress or chemotherapy, conflicting evidence remains regarding the validity of such a mechanism. Through comprehensive investigations in MYC-driven Colorectal Cancer (CRC) and Burkitt Lymphoma (BL) cells, we demonstrate that MYC UR does not facilitate cap-independent translation, but instead orchestrates resistance to PI3K inhibitors. Genomic deletion of MYC UR neither impacts MYC protein levels nor viability in CRC cells, either untreated or exposed to cellular stress. However, in response to PI3K inhibitors, MYC UR drives a FOXO3a-dependent transcriptional upregulation of MYC, conferring drug resistance. This resistance is mediated by enhanced autophagic flux, governed by MYC, and blockade of autophagy sensitizes CRC cells to PI3K inhibition in vitro and in vivo. Remarkably, BL cells lacking the translocation of MYC UR exhibit sensitivity to PI3K inhibitors, whereas MYC UR-translocated cells respond to these drugs only when autophagy is inhibited. These findings challenge previous notions regarding IRES-mediated translation and highlight a promising strategy to overcome resistance to PI3K inhibitors in MYC-driven malignancies, offering potential clinical implications for CRC and BL treatment. In response to BKM120, the upstream region of MYC (UR) enhances MYC expression, via FOXO3a, leading to increased autophagic flux and resistance to PI3K inhibitors (left). Pharmacological blockade of autophagy (center) or lack of translocated MYC UR along with MYC CDS in BL (right) overcome resistance and induces cells death. Image created in BioRender., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate All methods involving human derived materials and animal subjects were performed in accordance with the relevant local regulation and guidelines. All mouse experiments were performed according to the European Community Council Directive 2010/63/EU and carried out under the approval of the Institutional Animal Care Committee and Ministry of Health (protocol n. C1368.26). Patient-derived colorectal cancer stem cells were obtained in accordance with the ethical standards regarding Human Experimentation and informed consent was obtained from each patient in this study under Institutional Review Board protocols (authorization CE9/2015, Policlinico Paolo Giaccone, Palermo, Italy)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Non-small cell lung cancer (NSCLC) is a primary cause of cancer-related mortality on a global scale. Research increasingly shows that long non-coding RNAs (lncRNAs) play crucial regulatory roles and serve as biomarkers for diagnosis, prognosis, therapy monitoring, and druggable targets in NSCLC. We previously identified HAR1A as a tumor-suppressing lncRNA in NSCLC, with its loss also observed in oral and hepatocellular carcinoma. This study aimed to expand the understanding of the functional role of HAR1A in NSCLC and uncover its underlying mechanisms. Our results demonstrated that elevating HAR1A levels impeded NSCLC cell proliferation and migration but promoted apoptosis, thereby boosting their susceptibility to cisplatin. Subsequently, we discovered that HAR1A enhanced cisplatin's cytotoxicity in NSCLC cells by curbing adaptive autophagy through the downregulation of MYC. Further analysis revealed that HAR1A suppresses MYC by both lowering its transcript levels and promoting protein ubiquitination and degradation, thereby restricting tumor cell proliferation, migration, and adaptive autophagy. In exploring MYC's targets, we observed that MYC upregulated the transcription of heat shock protein 90 alpha family class B member 1 (HSP90AB1/HSP90β) gene. Rescue experiments verified that HAR1A mitigated NSCLC cell proliferation and migration and induced apoptosis through the MYC/HSP90β axis. Finally, we confirmed that HAR1A overexpression increased cisplatin efficacy in nude mouse NSCLC xenograft models.In conclusion, the findings suggest that HAR1A could be a promising therapeutic target in treating NSCLC and biomarkers for predicting chemotherapy outcomes. This study provides new insights into the molecular mechanisms of chemoresistance in NSCLC and underscores the potential of lncRNA-based strategies in cancer therapy., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Non-Hodgkin's lymphoma (NHL) is a significant global malignancy, with diffuse large B cell lymphoma (DLBCL) being the most prevalent subtype, accounting for 25-50 % of newly diagnosed cases in China. Despite a 60 % survival rate achieved with R-CHOP regiment for DLBCL, approximately 40 % of patients experience relapse or develop resistance to treatment. While the oncogenic transcription factor B-cell chronic lymphocytic leukaemia/lymphoma 11 A (BCL11A) has been implicated in various tumors, its specific role in DLBCL remains unclear. In this study, we conducted retrospective histomorphological and immunophenotypic analyses on paraffin sample tissues and collected fresh tissue samples for protein and mRNA analyses to investigate the relationship between BCL11A and DLBCL. Additionally, we classified DLBCL into subtypes based on cells of origin (COO) and examined the expressions of BCL11A, C-MYC, P53 and other protein expressions to better understand the factors contributing to poor clinical outcomes in DLBCL. Our findings revealed elevated BCL11A expression in DLBCL, with increased expression associated with worse prognosis and higher C-MYC expression. Patients exhibiting co-expression of C-MYC and BCL11A had significantly lower survival rates compared to those with singular expression. Furthermore, BCL11A protein expression levels demonstrated significant associations with P53 and C-MYC protein expression levels in the Germinal Center B-cell-like (GCB) subtype. These findings suggest that BCL11A may serve as a potential prognostic marker and therapeutic target for DLBCL., Competing Interests: Declaration of Competing Interest The authors declared that they have no conflict of interests., (Copyright © 2024. Published by Elsevier GmbH.)

Histone deacetylase 5 (HDAC5) is an enzyme that deacetylates lysine residues on the N-terminal of histones and other proteins. It has been reported that HDAC5 deacetylates p53, the critical factor regulating cell cycle, in response to cellular stress, but the transcriptional products haven't been identified. Herein, we used p53 signaling pathway qPCR-chip to determine how HDAC5-mediated deacetylation of p53 affects cell cycle. However, validation using immunoblotting analysis revealed that acetylation of p53 at K120 impacted little to the expression of the genes identified using the qPCR-chip, indicating HDAC5 might deacetylate some other proteins to facilitate cell cycle via transactivating the differentially expressed genes determined by the qPCR-chip. The subsequent assays demonstrated that HDAC5 deacetylated c-Myc at K143 and K157 to facilitate the transactivation of CDK1, CDK4, and CDC25C, promoting cell cycle progression of hepatocellular carcinoma (HCC). This study shows that HDAC5 plays important roles in modulating deacetylation of c-Myc and regulating cell cycle progression, and it proves that LMK-235, the inhibitor targeting HDAC5 potentially serves as a drug for combating HCC via promoting acetylation of c-Myc at K143 and K157., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Renal cell carcinoma (RCC) is a prevalent and aggressive kidney cancer with notable metastatic potential. While radiotherapy is effective for treating metastatic RCC, the emergence of radioresistance presents a major challenge. This study explores the role of DLX5 , previously identified as an oncogene in various cancers, in the development of radioresistance in RCC., Methods: Distal-less homeobox 5 (DLX5) expression was measured using western blot analysis. To study the effects of DLX5, its expression was knocked down in 786-O and Caki-1 RCC cell lines through si-DLX5 transfection, and the impact of DLX5 on RCC cell proliferation and radioresistance was assessed using cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assay, flow cytometry, colony formation, immunofluorescence, and western blot assays. The underlying mechanisms were explored through western blot, colony formation, and CCK-8 assays. In vivo effects were examined using a xenograft mouse model., Results: In silico results showed increased DLX5 levels in RCC tissues. Similarly, DLX5 expression was elevated in RCC cell lines. Silencing DLX5 reduced RCC cell proliferation and induced apoptosis in vitro . Additionally, DLX5 knockdown decreased radioresistance and increased DNA damage in RCC cells. Mechanistic studies revealed that DLX5 promotes radioresistance through the upregulation of c-Myc. In vivo , DLX5 silencing impeded tumor growth and reduced radioresistance., Conclusion: DLX5 contributes to RCC cell growth and radioresistance by upregulating c-Myc expression, highlighting its potential as a target for overcoming radioresistance in RCC., (© 2024 The Author(s). Published by IMR Press.)

Ovarian cancer, the eleventh most prevalent cancer among women and a significant cause of cancer-related mortality, poses considerable challenges. While the Myc oncogene is implicated in diverse cancers, its impact on tumours expressing Myc during immune therapy processes remains enigmatic. Our study investigated Myc overexpression in a murine ovarian cancer cell line, focusing on alterations in HIF1a function. Seahorse experiments were utilized to validate metabolic shifts post-Myc overexpression. Moreover, we explored macrophage polarization and immunosuppressive potential following coculture with Myc-overexpressing tumour cells by employing Gpr132 -/- mice to obtain mechanistic insights. In vivo experiments established an immune-competent tumour-bearing mouse model, and CD8 T cell, Treg, and macrophage infiltration post-Myc overexpression were evaluated via flow cytometry. Additionally, adoptive transfer of OTI CD8 T cells was conducted to investigate antigen-specific immune response variations after Myc overexpression. The findings revealed a noteworthy delay in HIF1a degradation, enhancing its functionality and promoting the classical Warburg effect upon Myc overexpression. Lactic acid secretion by Myc-overexpressing tumour cells promoted Gpr132-dependent M2 macrophage polarization, leading to the induction of macrophages capable of significantly suppressing CD8 T cell function. Remarkably, heightened macrophage infiltration in tumour microenvironments post-Myc overexpression was observed alongside impaired CD8 T cell infiltration and function. Interestingly, CD4 T-cell infiltration remained unaltered, and immune-suppressive effects were alleviated when Myc-overexpressing tumour cells were administered to Gpr132 -/- mice, shedding light on potential therapeutic avenues for ovarian cancer management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The overexpression of MYC genes is frequently found in many human cancers, including adult and pediatric malignant brain tumors. Targeting MYC genes continues to be challenging due to their undruggable nature. Using our prediction algorithm, the nine-amino-acid activation domain (9aaTAD) has been identified in all four Yamanaka factors, including c-Myc. The predicted activation function was experimentally demonstrated for all these short peptides in transactivation assay. We generated a set of c-Myc constructs (1-108, 69-108 and 98-108) in the N-terminal regions and tested their ability to initiate transcription in one hybrid assay. The presence and absence of 9aaTAD (region 100-108) in the constructs strongly correlated with their activation functions (5-, 3- and 67-times respectively). Surprisingly, we observed co-activation function of the myc region 69-103, called here acetyl-TAD, previously described by Faiola et al. (Mol Cell Biol 25:10220-10234, 2005) and characterized in this study as a new domain collaborating with the 9aaTAD. We discovered strong interactions on a nanomolar scale between the Myc-9aaTAD activation domains and the KIX domain of CBP coactivator. We showed conservation of the 9aaTADs in the MYC family. In summary for the c-Myc oncogene, the acetyl-TAD and the 9aaTAD domains jointly mediated activation function. The c-Myc protein is largely intrinsically disordered and therefore difficult to target with small-molecule inhibitors. For the c-Myc driven tumors, the strong c-Myc interaction with the KIX domain represents a promising druggable target., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors have no competing interests to declare., (© 2024. The Author(s).)

Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and in vivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming., Competing Interests: Declaration of interests J.C. is a founder and shareholder in Moonlight Bio., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Myc proteins are transcription factors crucial for cell proliferation. They have a C-terminal domain that mediates Max and DNA binding, and an N-terminal disordered region culminating in the transactivation domain (TAD). The TAD participates in many protein-protein interactions, notably with kinases that promote stability (Aurora-A) or degradation (ERK1, GSK3) via the ubiquitin-proteasome system. We probed the structure, dynamics and interactions of N-myc TAD using nuclear magnetic resonance (NMR) spectroscopy following its complete backbone assignment. Chemical shift analysis revealed that N-myc has two regions with clear helical propensity: Trp77-Glu86 and Ala122-Glu132. These regions also have more restricted ps-ns motions than the rest of the TAD, and, along with the phosphodegron, have comparatively high transverse (R2) 15N relaxation rates, indicative of slower timescale dynamics and/or chemical exchange. Collectively these features suggest differential propensities for structure and interaction, either internal or with binding partners, across the TAD. Solution studies on the interaction between N-myc and Aurora-A revealed a previously uncharacterised binding site. The specificity and kinetics of sequential phosphorylation of N-myc by ERK1 and GSK3 were characterised using NMR and resulted in no significant structural changes outside the phosphodegron. When the phosphodegron was doubly phosphorylated, N-myc formed a robust interaction with the Fbxw7-Skp1 complex, but mapping the interaction by NMR suggests a more extensive interface. Our study provides foundational insights into N-myc TAD dynamics and a backbone assignment that will underpin future work on the structure, dynamics, interactions and regulatory post-translational modifications of this key oncoprotein., (© 2024 The Author(s).)

Background/aim: Non-small-cell lung cancer (NSCLC) comprises approximately 85% of lung cancer. Treatment with docetaxel prolongs the survival of patients with NSCLC. However, the development of resistance to docetaxel has compromised its efficacy. Caffeic acid phenethyl ester (CAPE) has been reported to suppress survival and radiotherapy resistance in lung cancer cells. We determined in this study if combination treatment of docetaxel with CAPE suppresses the proliferation and the survival of NSCLC cells more effectively., Materials and Methods: Proliferation, viability, flow cytometric and comet assays were used to examine the difference in anticancer effects of combined treatment as compared to docetaxel treatment alone. Western blot and gene overexpression were used to unravel the underlying molecular mechanism., Results: Treatment with docetaxel or CAPE alone dose-dependently suppressed the proliferation and survival of H1299 and A549 cells. Combined treatment of docetaxel with CAPE caused greater inhibition of survival of H1299 and A549 cells. Docetaxel alone and the combined treatment both dose-dependently increased apoptosis of H1299 cells; however, combined treatment induced much more apoptosis than docetaxel alone. Combined treatment suppressed the protein expression of phospho-protein kinase B (AKT, Ser 473), S-phase protein 2 (SKP2), MYC proto-oncogene bHLH transcription factor (c-MYC), epidermal growth factor receptor (EGFR), phospho-EGFR (Tyr 1045, and Tyr 992) but increased levels of cleaved caspase 3 and cytochrome c proteins in H1299 and A549 cells. The inhibition of expression of SKP2, c-MYC, phospho-EGFR (Tyr 992) proteins by combined treatment was significantly greater than that with treatment using either CAPE or docetaxel alone. Overexpression of c-MYC in rescued proliferation of H1299 cells under combination treatment., Conclusion: Our study revealed that the combination of CAPE with docetaxel is more effective at reducing the proliferation and survival of NSCLC cells, and this is via inhibition of c-MYC. Combined therapy of docetaxel and CAPE may benefit patients with NSCLC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Ubiquitination is an important post-transcriptional modification crucial for maintaining cell homeostasis. As a deubiquitination enzyme, ubiquitin-specific protease 1 (USP1) is associated with tumor progression; however, its role in bladder cancer is unknown. This study aimed to analyze USP1 expression and study its roles in bladder cancer., Methods: The web server GEPIA was used to analyze the USP1 expression. To explore USP1's function in bladder cancer, we constructed USP1-knockout cell lines in UMUC3 cells. A FLAG-USP1 (WT USP1) plasmid and a plasmid FLAG-USP1 C90S (catalytic-inactive mutant) were used to overexpress USP1 in T24 cells. CCK8, colony formation, and Transwell assays were used to assess cell viability, proliferation, and migration. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays were performed to screen the pathway. Co-immunoprecipitation and immunofluorescence were used to explore the interaction between USP1 and c-MYC. A xenograft mouse model was used to study the role of USP1 in bladder cancer., Results: USP1 expression was upregulated in human bladder cancer cells and correlated with poor patient prognosis. USP1 overexpression promoted cell proliferation, clone formation, and migration, and this was attenuated by genetic ablation of USP1. Furthermore, we observed that USP1 deficiency inhibited tumor formation in vivo. Mechanistically, the c-MYC pathway was remarkably activated compared with the other pathways. Furthermore, USP1 could interact with c-MYC and increase c-MYC's stability depending on the catalytic activity of USP1., Conclusions: Our results suggested that high expression of USP1 promotes bladder cancer progression by stabilizing c-MYC; hence, USP1 may serve as a novel therapeutic target for treating bladder cancer.

The dysfunction of the ubiquitin-proteasome system (UPS) facilitates the malignant progression of hepatocellular carcinoma (HCC). While targeting the UPS for HCC therapy has been proposed, identifying effective targets has been challenging. In this study, we conducted a focused screen of siRNA libraries targeting UPS-related WD40 repeat (WDR) proteins and found that silencing WDR20, a deubiquitinating enzyme activating factor, selectively inhibited the proliferation of HCC cells without affecting normal hepatocytes. Moreover, the downregulation of WDR20 expression induced HCC cellular senescence and suppressed tumor progression in xenograft, sleeping beauty transposon/transposase, and hydrodynamic tail vein injection-induced HCC models, and Alb-Cre + HCC transgenic mouse models. Mechanistically, we found that WDR20 silencing disturbed the protein stability of c-Myc, orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc, thereby promoting the transcriptional activation of MYC . Further investigation revealed a positive coexpression of WDR20 and c-Myc in a tissue microarray with 88 HCC clinical samples. By employing three patient-derived organoids from individuals with HCC, we have validated the decrease in c-Myc expression and the significant induction of senescence and growth inhibition following silencing of WDR20. This study not only uncovers the biological function of WDR20 and elucidates the molecular mechanism underlying its negative regulation of HCC cellular senescence but also highlight the potential of WDR20 as a promising target for HCC therapy.+ HCC transgenic mouse models. Mechanistically, we found that WDR20 silencing disturbed the protein stability of c-Myc, orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc, thereby promoting the transcriptional activation of CDKN1A . Further investigation revealed a positive coexpression of WDR20 and c-Myc in a tissue microarray with 88 HCC clinical samples. By employing three patient-derived organoids from individuals with HCC, we have validated the decrease in c-Myc expression and the significant induction of senescence and growth inhibition following silencing of WDR20. This study not only uncovers the biological function of WDR20 and elucidates the molecular mechanism underlying its negative regulation of HCC cellular senescence but also highlight the potential of WDR20 as a promising target for HCC therapy., Competing Interests: Competing interests statement:The authors declare no competing interest.

Introduction : KRAS and MYC are proto-oncogenes that are strictly regulated in healthy cells that have key roles in several processes such as cell growth, proliferation, differentiation, or apoptosis. These genes are tightly interconnected, and their dysregulation can lead to cancer progression. We previously individually targeted these oncogenes using Polypurine Reverse Hoogsteen (PPRH) hairpins, mostly targeting the complementary strand of G-quadruplex-forming sequences. We validated them in vitro in different cancer cell lines with deregulated KRAS and/or MYC. In this work we focused on our understanding of the cooperative dynamics between these oncogenes, by investigating the combined impact of PPRHs targeting KRAS and MYC in pancreatic and prostate cancer cells. Results : The combinations had a modulatory impact on the expression of both oncogenes, with transcriptional and translational downregulation occurring five days post-treatment. Out of the four tested PPRHs, MYC-targeting PPRHs, especially HpMYC-G4-PR-C directed against the promoter, showed a greater cytotoxic and expression modulation effect. When both KRAS- and MYC-targeting PPRHs were applied in combination, a synergistic reduction in cell viability was observed. Conclusion : The simultaneous targeting of KRAS and MYC demonstrates efficacy in gene modulation, thus in decreasing cell proliferation and viability.

Kirsten rat sarcoma virus (KRAS) mutation is associated with malignant tumor transformation and drug resistance. However, the development of clinically effective targeted therapies for KRAS-mutant cancer has proven to be a formidable challenge. Here, we report that tripartite motif-containing protein 21 (TRIM21) functions as a target of extracellular signal-regulated kinase 2 (ERK2) in KRAS-mutant colorectal cancer (CRC), contributing to regorafenib therapy resistance. Mechanistically, TRIM21 directly interacts with and ubiquitinates v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) at lysine 148 (K148) via K63-linkage, enabling c-Myc to be targeted to the autophagy machinery for degradation, ultimately resulting in the downregulation of enolase 2 expression and inhibition of glycolysis. However, mutant KRAS (KRAS/MT)-driven mitogen-activated protein kinase (MAPK) signaling leads to the phosphorylation of TRIM21 (p-TRIM21) at Threonine 396 (T396) by ERK2, disrupting the interaction between TRIM21 and c-Myc and thereby preventing c-Myc from targeting autophagy for degradation. This enhances glycolysis and contributes to regorafenib resistance. Clinically, high p-TRIM21 (T396) is associated with an unfavorable prognosis. Targeting TRIM21 to disrupt KRAS/MT-driven phosphorylation using the antidepressant vilazodone shows potential for enhancing the efficacy of regorafenib in treating KRAS-mutant CRC in preclinical models. These findings are instrumental for KRAS-mutant CRC treatment aiming at activating TRIM21-mediated selective autophagic degradation of c-Myc., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: This study investigated the expression and role of Synaptosome associated protein 25 (SNAP25) in high-grade neuroendocrine carcinoma (HGNEC)., Methods: We used differentially expressed analysis and weighted gene co-expression network analysis (WGCNA) to identify key genes and modules in HGNEC. KEGG and GO analyses helped understand these genes' roles, and ROC curves assessed their diagnostic value. We also studied SNAP25's relation to immune infiltration and confirmed findings with in vitro and vivo experiments and datasets., Results: WGCNA identified 595 key genes related to pathways like MAPK signaling, GABAergic synapse, and cancer-related transcriptional misregulation. Top genes included SNAP25, MYC, NRXN1, GAD2, and SYT1. SNAP25 was notably associated with M2 macrophage infiltration. Dataset GSE40275 confirmed SNAP25's high expression and poor prognosis in HGNEC. qRT-PCR and WB analyses showed increased SNAP25 and c-MYC levels in HGNEC, promoting MEK/ERK pathway activity. Reducing SNAP25 decreased H1299 cell proliferation, migration, invasion, and levels of c-MYC, MEK, and ERK. Finally, in vivo experiments further confirmed that SNAP25 knockout can inhibit tumor growth., Conclusion: SNAP25 regulates c-MYC activation by stimulating the MEK/ERK pathway, ultimately influencing the development of HGNEC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Wang, Wang, Wang, Qi, An, Sun and Lin.)

MYC has been implicated in the pathogenesis of a wide range of human tumors and has been described for many years as a transcription factor that regulates genes with pleiotropic functions to promote tumorigenic growth. However, despite extensive efforts to identify specific target genes of MYC that alone could be responsible for promoting tumorigenesis, the field is yet to reach a consensus whether this is the crucial function of MYC. Recent work shifts the view on MYC's function from being a gene-specific transcription factor to an essential stress resilience factor. In highly proliferating cells, MYC preserves cell integrity by promoting DNA repair at core promoters, protecting stalled replication forks, and/or preventing transcription-replication conflicts. Furthermore, an increasing body of evidence demonstrates that MYC not only promotes tumorigenesis by driving cell-autonomous growth, but also enables tumors to evade the host's immune system. In this review, we summarize our current understanding of how MYC impairs antitumor immunity and why this function is evolutionarily hard-wired to the biology of the MYC protein family. We show why the cell-autonomous and immune evasive functions of MYC are mutually dependent and discuss ways to target MYC proteins in cancer therapy., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background & Aims: WNT signaling is central to spatial tissue arrangement and regulating stem cell activity, and it represents the hallmark of gastrointestinal cancers. Although its role in driving intestinal tumors is well characterized, WNT's role in gastric tumorigenesis remains elusive., Methods: We have developed mouse models to control the specific expression of an oncogenic form of β-catenin (CTNNB1) in combination with MYC activation in Lgr5 + cells of the gastric antrum. We used multiomics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis., Results: We report that constitutive β-catenin stabilization in the stomach has negligible oncogenic effects and requires MYC activation to induce gastric tumor formation. Although physiologically low MYC levels in gastric glands limit β-catenin transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting β-catenin enhancer invasion without a direct transcriptional cooperation. MYC activation induces a metabolic rewiring that suppresses lysosomal biogenesis through mTOR and ERK activation and MiT/TFE inhibition. This prevents EPCAM degradation by macropinocytosis, promoting β-catenin chromatin accumulation and activation of WNT oncogenic transcription., Conclusion: Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of MYCN expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell-intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I-like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic MYCN transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, but effective therapeutic strategies are limited. Transcriptional factor c-Myc plays an oncogenic role in tumorigenesis and is an attractive target for HCC treatment. However, targeted therapy against c-Myc remains challenging. Herein, by conjugating VH032 with an optimized DNA sequence that recognized c-Myc complex, we discovered oligonucleotide-based proteolysis targeting chimeras (PROTACs), termed as MP-16 and MP-17, which effectively induced degradation of c-Myc. Mechanically, MP-16 or MP-17 directly interacted with c-Myc complex to form VHL/PROTAC/c-Myc ternary complex, and triggered c-Myc degradation by recruiting ubiquitin-proteasome system, suppressing cell proliferation of HCC cells. In mice model, MP-16 or MP-17 significantly inhibited HCC tumor growth and exhibited promising drug safety. This work provided novel oligonucleotide PROTACs that degraded c-Myc, giving a new lead structure for HCC therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Psoriasis is a chronic inflammatory skin disease characterized by a complex pathogenesis involving various types of cells and cytokines. Among those, the pro-inflammatory cytokine IL-23/IL-17A axis plays a crucial role in the development and rapid progression of psoriasis. Phenformin, a derivative of metformin and a member of the biguanide class of drugs, exhibits superior anti-inflammatory and anti-tumor efficacy compared to metformin. However, the potential role of phenformin in anti-psoriatic skin inflammation has not been explored., Methods: In this study, we utilized a mouse model of psoriasis and an in vitro model using human keratinocytes to investigate whether phenformin can suppress psoriasis-like inflammatory responses., Results: Our results demonstrate that the topical application of phenformin significantly inhibited acute skin inflammatory responses in the psoriasis mouse model induced by imiquimod (IMQ). Additionally, phenformin suppressed the expression of psoriasis-related cytokines IL-17, IL-23, IL-8, and S100A8/S100A9 in an in vitro psoriatic keratinocyte model induced by IMQ. Furthermore, we found that IMQ-induced psoriatic skin and IMQ-treated keratinocytes exhibited high expression of the c-Myc gene, which was downregulated by phenformin. The c-Myc inhibitor JQ1 similarly inhibited the psoriatic inflammatory response and the expression of psoriasis-related cytokines in both in vitro and in vivo models., Conclusion: phenformin ameliorates the psoriasis-like inflammatory response by inhibiting c-Myc expression in keratinocytes, suggesting its potential as a topical drug for the treatment of psoriasis., Competing Interests: Declaration of competing interest All authors declare no potential conflict of interest with respect to the research, authorship and publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Glioblastoma (GBM) is a brain tumor with poor prognosis. Dexmedetomidine (Dex) regulates the biological behaviors of tumor cells to accelerate or decelerate cancer progression., Objective: We investigated the effects of Dex on the migration, invasion, and glycolysis in GBM., Methods: The concentration of Dex was determined using the cell counting kit-8 assay. The impacts of Dex on biological behaviors of GBM cells were assessed using Transwell assay, XF96 extracellular flux analysis, and western blot. The expression of c-Myc was examined using reverse transcription-quantitative polymerase chain reaction. The lactylation or stability of c-Myc was measured by western blot after immunoprecipitation or cycloheximide treatment., Results: We found that Dex (200 nM) inhibited GBM cell viability, migration, invasion, and glycolysis. C-Myc was highly expressed in GBM cells and was decreased by Dex treatment. Moreover, Dex suppressed lactylated c-Myc levels via suppressing glycolysis, thereby reducing the protein stability of c-Myc. Sodium lactate treatment abrogated the effects of Dex on the biological behaviors of GBM cells., Conclusion: Dex suppressed the migration, invasion, and glycolysis of GBM cells via inhibiting lactylation of c-Myc and suppressing the c-Myc stability, suggesting that Dex may be a novel therapeutic drug for GBM treatment.

Alteration or abnormal activation of RTKs have been recurrently observed and recognized as an important driving factor in the progression of many human cancers. Ferroptosis, an iron-dependent form of regulated necrosis triggered by the accumulation of lethal lipid peroxides on cell membranes, has been implicated in various tumor types. Here we reported that oncogenic RTKs/RAS/RAF/c-Myc axis promotes cancer cells to ferroptosis. Mechanistically, c-Myc binds to the promoter region of ACSL4 and promotes the expression of ACSL4, thereby sensitizes cells to ferroptosis. We further showed that RTKs/RAS/RAF promote ferroptosis by upregulating c-Myc mediated expression of ACSL4 in cancer cells. Notably, overexpression of RTKs enhances the vulnerability of melanoma to the ferroptosis inducer in mouse xenograft model. These findings may provide an attractive intervention strategy to target cancers with oncogenic activation of RTKs via a ferroptosis-inducing approach., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: All animal experiments were performed in accordance with the approved protocols of the Animal Experimentation Rules issued by the Chinese government (Beijing, China) and approved by the Research Ethics Committee of Harbin Institute of Technology., (© 2024. The Author(s).)

High-grade osteosarcoma (OS) is the most common primary bone tumor mainly affecting children and young adults. First-line treatment consists of neo-adjuvant chemotherapy with doxorubicin, cisplatin, and methotrexate and surgery. The mean long-term survival rate for localized disease at diagnosis is 65-70%, dropping down to 20% when metastases are present at diagnosis. Therefore, curing OS is a clinical challenge, particularly for patients that do not respond to standard treatments. MYC has frequently been reported to be involved in the pathogenesis of OS and its high expression may be associated with drug resistance and patients' worse prognosis. Moreover, MYC is a master regulator of ribosomal proteins (RPs) synthesis and ribosome biogenesis (RiBi), which is often up-regulated in human tumors. In recent years, RPs have been recognized not only for their traditional role in ribosome assembly but also for their extra-ribosomal functions, many of which are linked to the onset and progression of cancer. In this review we focus on the role and possible interplay of MYC and RPs expression in association with drug resistance and worse prognosis in OS and discuss therapeutic options that target de-regulated MYC , RiBi, or RPs, which are already clinically available or under evaluation in clinical trials.

Heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) is considered a cancer-promoting heterogeneous nuclear ribonucleoprotein in many cancers, but its function in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. hnRNPAB was highly expressed in PDAC tissues compared with normal pancreatic tissues, and high expression of hnRNPAB was associated with poor overall survival and recurrence-free survival in patients with PDAC. hnRNPAB promotes migration and invasion of PDAC cells in vitro. In xenograft tumor mouse models, hnRNPAB deprivation significantly attenuated liver metastasis. hnRNPAB mRNA and protein levels are positively associated with MYC in PDAC cells. Mechanistically, hnRNPAB bound to MYC mRNA and prolonged its half-life. hnRNPAB induced PDAC cells to secrete CXCL8 via MYC, which promoted neutrophil recruitment and facilitated tumor cells entrancing into the hepatic parenchyma. These findings point to a novel regulatory mechanism via which hnRNPAB promotes PDAC metastasis. Implications: hnRNPAB participates in the posttranscriptional regulation of the oncogene MYC by binding and stabilizing MYC mRNA, thereby promoting liver metastasis in PDAC., (©2024 American Association for Cancer Research.)

Acute lymphoblastic leukemia is a challenging disease to treat, especially in older adults who are most commonly diagnosed and have a high risk of relapse, even with current treatment options. MST-312, targets the RNA component of telomerase, inhibiting its activity and leading to growth arrest and telomere shortening in cancer cells. This study aimed to investigate the effects of MST-312 on apoptosis rates and the expression of telomerase target genes, CCND1, MDM2, MYC, and HSP90AA1, in Jurkat cell line. Jurkat cell line was cultured and treated with various concentrations of MST-312(0 µM, 0.5 µM, 1 µM, 2 µM, and 4 µM). The optimal concentration of MST-312 was determined using MTT assay. Flow cytometry was employed to evaluate the apoptosis induced by MST-312 treatment. The expression levels of the target genes were measured using real-time polymerase chain reaction before and after the treatment with MST-312. P-value < 0.05 was considered statistically significant. The percentages of apoptotic cells after 48 h, as determined by flow cytometry analysis, were 30.32%, 52.35%, 57.60%, and 68.82%, respectively, compared to the control group which was 4.6%. The expression levels of all genes, including CCND1, MDM2, MYC, and HSP90AA1, were decreased compared to the control group. The results showed that MST-312 induced dose- and time-dependent apoptosis and downregulated the expression of CCND1, MDM2, MYC, and HSP90AA1in Jurkat cell line., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Prostate cancer (PCa) is the most frequently diagnosed malignant tumor in males, and there are currently few effective therapeutic targets following hormone therapy resistance. Subunits of eukaryotic initiation factor 3 (eIF3) have been implicated in the progression of various cancers. This study aims to investigate the biological functions of the eIF3m subunit in PCa and assess its potential as a novel therapeutic target for treatment. We utilized open-access datasets and patient tissues to analyze the expression and prognostic value of eIF3m in PCa. To explore the role of eIF3m in PCa growth, we established eIF3m knockdown models in PC3 and 22Rv1 cells for both in vitro and in vivo studies. Gene set enrichment analysis (GSEA) was utilized to identify signaling pathways regulated by eIF3m in PCa. Additionally, western blotting and immunochemistry were used to confirm the regulation of c-Myc signaling by eIF3m in PCa. Our results indicated that eIF3m expression was elevated in PCa tissues, with higher levels correlating with an increased risk of biochemical recurrence following radical prostatectomy. Both in vitro and in vivo experiments demonstrated that inhibiting eIF3m significantly impeded the growth of PCa cells. GSEA and immunochemistry further revealed that high eIF3m expression contributed to the activation of c-Myc signaling in PCa patients. Notably, the downregulation of eIF3m resulted in a significant decrease in the expression of c-Myc mRNA and protein in PCa cells. Overall, our findings suggest that eIF3m inhibition significantly suppressed PCa cell growth and c-Myc signaling, indicating that eIF3m is a promising therapeutic target for PCa patients.

c-MYC is one of the most important oncogenes, which is overexpressed in many cancers, and is highly related to development, metastasis, and drug resistance of cancers. The G4 structure in the promoter of c-MYC oncogene contributes a lot to the gene transcriptional mechanism. Small-molecule ligands binding to the c-MYC G4 appear to be a new class of anticancer agents. However, selective ligands for the c-MYC G4 over other G4s have been rarely reported. In this study, we reported a novel fluorescent ligand by migrating the benzene group on a carbazole-benzothiazolium scaffold, which was demonstrated to exhibit considerable specificity to the c-MYC G4, which was distinguished from other small-molecule ligands. The further cellular experiments suggested that this ligand may indeed target the promoter G4 and cause apparent transcriptional inhibition of the c-MYC oncogene instead of other G4-mediated oncogenes, which thereby resulted in cancer cell growth inhibition. Collectively, this study provided a good example for developing specific c-MYC G4 ligands, which may further develop into an effective anticancer agent that inhibit the c-MYC expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an aggressive sub-group of castration-resistant prostate cancer (CRPC). Hyper-activation of MYC transcription factor is sufficient to confer the CRPC phenotype. Here, we show that loss of CDK12 promotes MYC activity, which renders the cells dependent on the otherwise non-essential splicing regulatory kinase SRSF protein kinase 1 (SRPK1). High MYC expression is associated with increased levels of SRPK1 in patient samples, and overexpression of MYC sensitizes prostate cancer cells to SRPK1 inhibition using pharmacological and genetic strategies. We show that Endovion (SCO-101), a compound currently in clinical trials against pancreatic cancer, phenocopies the effects of the well-characterized SRPK1 inhibitor SRPIN340 on nascent transcription. This is the first study to show that Endovion is an SRPK1 inhibitor. Inhibition of SRPK1 with either of the compounds promotes transcription elongation, and transcriptionally activates the unfolded protein response. In brief, here we discover that CDK12 inactivation promotes MYC signaling in an SRPK1-dependent manner, and show that the clinical grade compound Endovion selectively targets the cells with CDK12 inactivation., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Cholangiocarcinoma (CCA), a malignancy that arises from biliary epithelial cells, has a dismal prognosis, and few targeted therapies are available. Aurora B, a key mitotic regulator, has been reported to be involved in the progression of various tumors, yet its role in CCA is still unclarified., Methods: Human CCA tissues and murine spontaneous CCA models were used to assess Aurora B expression in CCA. A loss-of-function model was constructed in CCA cells to determine the role of Aurora B in CCA progression. Subcutaneous and liver orthotopic xenograft models were used to assess the therapeutic potential of Aurora B inhibitors in CCA., Results: In murine spontaneous CCA models, Aurora B was significantly upregulated. Elevated Aurora B expression was also observed in 62.3% of human specimens in our validation cohort (143 CCA specimens), and high Aurora B expression was positively correlated with pathological parameters of tumors and poor survival. Knockdown of Aurora B by siRNA and heteroduplex oligonucleotide (HDO) or an Aurora B kinase inhibitor (AZD1152) significantly suppressed CCA progression via G2/M arrest induction. An interaction between Aurora B and c-Myc was found in CCA cells. Targeting Aurora B significantly reduced this interaction and accelerated the proteasomal degradation of c-Myc, suggesting that Aurora B promoted the malignant properties of CCA by stabilizing c-Myc. Furthermore, sequential application of AZD1152 or Aurora B HDO drastically improved the efficacy of gemcitabine in CCA., Conclusions: Aurora B plays an essential role in CCA progression by modulating c-Myc stability and represents a new target for treatment and chemosensitization in CCA., (© 2023 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Aggressive B-cell non-Hodgkin lymphomas (NHL) in children, adolescents, and young adults (CAYA) include Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and a subset of high-grade tumors with features intermediate between these entities whose genetic and molecular profiles have not been completely elucidated. In this study, we have characterized 37 aggressive B-NHL in CAYA, 33 with high-grade morphology, and 4 DLBCL with MYC rearrangement (MYC-R), using targeted next-generation sequencing and the aggressive lymphoma gene expression germinal center B-cell-like (GCB), activated B-cell-like (ABC), and dark zone signatures (DZsig). Twenty-two tumors had MYC-R without BCL2 breaks, and two MYC-non-R cases had BCL6 translocations. MYC-R cases, including DLBCL, carried BL-related mutations and copy number alterations. Conversely, MYC-non-R lymphomas had alterations in the B-cell receptor signaling/NF-κB pathway (71%). DZsig was expressed in 12/13 of MYC-R tumors but only in 2/10 of MYC-non-R GCB tumors (P < 0.001). The 3-year event-free survival (EFS) of the whole cohort was 79.6%. TP53 and KMT2C mutations conferred inferior outcome (3-year EFS P < 0.05). Overall, MYC-R lymphomas in CAYA have a molecular profile similar to BL regardless of their high-grade or DLBCL morphology, whereas MYC-non-R has more heterogeneous genetic alterations closer to that of DLBCL., (© 2024. The Author(s).)

MYC-rearranged high-grade B-cell lymphoma (HGBCL) patients with concurrent BCL2 rearrangements (HGBCL-MYC/BCL2) often have a poor prognosis with standard chemoimmunotherapy and may benefit from more intensified regimens. Conventional fluorescence in situ hybridization (FISH) is the gold standard for detecting rearrangements, but it has several limitations. This study compared DNA- and RNA-sequencing with FISH to detect clinically relevant rearrangements in HGBCL. Archived formalin-fixed, paraffin-embedded samples from 34 patients who underwent FISH testing were analyzed using targeted DNA- and RNA-sequencing. DNA- and RNA-sequencing identified six and five out of the 12 MYC rearrangements detected by FISH, 10 and 6 out of 10 FISH-detectable BCL2 rearrangements, and 13 and 10 out of the 18 FISH-detectable BCL6 rearrangements. When combining DNA- and RNA-sequencing (integrated NGS), the sensitivity for detecting MYC, BCL2, and BCL6 rearrangements was 58.3%, 100%, and 73.7%, respectively. Both DNA- and RNA-sequencing detected the EIF4A2::BCL6 fusion missed by FISH. FISH identified 12 HGBCL-MYC/BCL2 out of 34 cases, while the integrated NGS strategy identified 7 cases, with 5 cases showing discordant results (41.7%). Additionally, patients with DLBCL/HGBCL-MYC/BCL2 had significantly shorter overall survival than other patients. Our results suggest that an integrated NGS strategy should not replace FISH or be routinely used in the workup to detect the clinically relevant rearrangements in HGBCL. It may serve as a complement to FISH testing when FISH shows negative results.

The critical role of c-Myc as a driving factor in the development and progression of lung cancer establishes it as a pivotal target for anti-lung cancer therapeutic research. In our previous study, we reported on the discovery of D347-2761, a novel small-molecule inhibitor that specifically targets the unstable domain of c-Myc and disrupts the c-Myc/Max heterodimer. To enhance targeted therapies further, we conducted an extensive structural analysis and designed a series of innovative benzimidazole derivatives. The cytotoxic activities of these compounds were assessed using the CCK-8 assay, revealing that compound A1 displayed IC 50 values of 6.32 μM and 11.39 μM against the A549 and NCI-H1299 lung cancer cell lines, respectively, while compound A5 exhibited IC 50 values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds A1 and A5 exhibited potent anticancer activity by disrupting the interaction between c-Myc and Max proteins, leading to the downregulation of c-Myc protein levels and induction of apoptosis through apoptotic pathways. Notably, compound A5 demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound A5 exhibited excellent efficacy with a tumor growth inhibition rate reaching up to 76.4 %, accompanied by a significant reduction in c-Myc protein expression levels. Therefore, compound A5 holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)