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4. A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation

Author

Hess, Lena, primary, Moos, Verena, additional, Lauber, Arnel A., additional, Reiter, Wolfgang, additional, Schuster, Michael, additional, Hartl, Natascha, additional, Lackner, Daniel, additional, Boenke, Thorina, additional, Koren, Anna, additional, Guzzardo, Paloma M., additional, Gundacker, Brigitte, additional, Riegler, Anna, additional, Vician, Petra, additional, Miccolo, Claudia, additional, Leiter, Susanna, additional, Chandrasekharan, Mahesh B., additional, Vcelkova, Terezia, additional, Tanzer, Andrea, additional, Jun, Jun Qi, additional, Bradner, James, additional, Brosch, Gerald, additional, Hartl, Markus, additional, Bock, Christoph, additional, Bürckstümmer, Tilmann, additional, Kubicek, Stefan, additional, Chiocca, Susanna, additional, Bhaskara, Srividya, additional, and Seiser, Christian, additional

Published
2022
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6. Hdac3 Is Essential for the Maintenance of Chromatin Structure and Genome Stability

Author

Bhaskara, Srividya, Knutson, Sarah K., Jiang, Guochun, Chandrasekharan, Mahesh B., Wilson, Andrew J., Zheng, Siyuan, Yenamandra, Ashwini, Locke, Kimberly, Yuan, Jia-ling, Bonine-Summers, Alyssa R., Wells, Christina E., Kaiser, Jonathan F., Washington, M. Kay, Zhao, Zhongming, Wagner, Florence F., Sun, Zu-Wen, Xia, Fen, Holson, Edward B., Khabele, Dineo, and Hiebert, Scott W.

Published
2010
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7. HDAC3 is essential for DNA replication in hematopoietic progenitor cells

Author

Summers, Alyssa R., Fischer, Melissa A., Stengel, Kristy R., Zhao, Yue, Kaiser, Jonathan F., Wells, Christina E., Hunt, Aubrey, Bhaskara, Srividya, Luzwick, Jessica W., Sampathi, Shilpa, Chen, Xi, Thompson, Mary Ann, Cortez, David, and Hiebert, Scott W.

Subjects
Gene expression -- Physiological aspects -- Analysis -- Health aspects, DNA replication -- Physiological aspects -- Analysis, Leukemia -- Genetic aspects -- Care and treatment, Lymphomas -- Genetic aspects -- Care and treatment, Genetic engineering -- Health aspects, Health care industry
Abstract

Histone deacetylase 3 (HDAC3) contributes to the regulation of gene expression, chromatin structure, and genomic stability. Because HDAC3 associates with oncoproteins that drive leukemia and lymphoma, we engineered a conditional [...]

Published
2013
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9. Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug

Author

Girard, Pierre‐Marie, Berthault, Nathalie, Kozlac, Maria, Ferreira, Sofia, Jdey, Wael, Bhaskara, Srividya, Alekseev, Sergey, Thomas, Frédéric, Dutreix, Marie, Institut Curie [Orsay], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

13. Mechanistic basis and efficacy of targeting the β-catenin–TCF7L2–JMJD6–c-Myc axis to overcome resistance to BET inhibitors

Author

Saenz, Dyana T., primary, Fiskus, Warren, primary, Mill, Christopher P., primary, Perera, Dimuthu, primary, Manshouri, Taghi, primary, Lara, Bernardo H., primary, Karkhanis, Vrajesh, primary, Sharma, Sunil, primary, Horrigan, Stephen K., primary, Bose, Prithviraj, primary, Kadia, Tapan M., primary, Masarova, Lucia, primary, DiNardo, Courtney D., primary, Borthakur, Gautam, primary, Khoury, Joseph D., primary, Takahashi, Koichi, primary, Bhaskara, Srividya, primary, Lin, Charles Y., primary, Green, Michael R., primary, Coarfa, Cristian, primary, Crews, Craig M., primary, Verstovsek, Srdan, primary, and Bhalla, Kapil N., primary

Published
2020
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20. Mechanistic basis and efficacy of targeting the ß-catenin–TCF7L2–JMJD6–c-Myc axis to overcome resistance to BET inhibitors

Author

Saenz, Dyana T., Fiskus, Warren, Mill, Christopher P., Perera, Dimuthu, Manshouri, Taghi, Lara, Bernardo H., Karkhanis, Vrajesh, Sharma, Sunil, Horrigan, Stephen K., Bose, Prithviraj, Kadia, Tapan M., Masarova, Lucia, DiNardo, Courtney D., Borthakur, Gautam, Khoury, Joseph D., Takahashi, Koichi, Bhaskara, Srividya, Lin, Charles Y., Green, Michael R., Coarfa, Cristian, Crews, Craig M., Verstovsek, Srdan, and Bhalla, Kapil N.

Abstract

The promising activity of BET protein inhibitors (BETi’s) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/enhancers, which was associated with increased levels of nuclear ß-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the ß-catenin–TCF7L2–JMJD6–c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear ß-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the ß-catenin–TCF7L2–JMJD6–c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.

Published
2020
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24. Interaction of the Jhd2 Histone H3 Lys-4 Demethylase with Chromatin Is Controlled by Histone H2A Surfaces and Restricted by H2B Ubiquitination

Author

Huang, Fu, primary, Ramakrishnan, Saravanan, additional, Pokhrel, Srijana, additional, Pflueger, Christian, additional, Parnell, Timothy J., additional, Kasten, Margaret M., additional, Currie, Simon L., additional, Bhachech, Niraja, additional, Horikoshi, Masami, additional, Graves, Barbara J., additional, Cairns, Bradley R., additional, Bhaskara, Srividya, additional, and Chandrasekharan, Mahesh B., additional

Published
2015
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25. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-kappaB

Author

Ziesché, Elisabeth, Kettner-Buhrow, Daniela, Weber, Axel, Wittwer, Tobias, Jurida, Liane, Soelch, Johanna, Müller, Helmut, Newel, Doris, Kronich, Petra, Schneider, Heike, Dittrich-Breiholz, Oliver, Bhaskara, Srividya, Hiebert, Scott W., Hottiger, Michael O., Li, Haiying, Burstein, Ezra, Schmitz, M. Lienhard, Kracht, Michael, and Justus Liebig University Giessen

Subjects
ddc:610, histone deacetylase 3 (HDAC3), NF-kappaB p65, positive gen-regulation of IL-1, co-activator in inflammatory signaling pathways
Abstract

Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes containing silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a positive regulator of IL-1-induced gene expression. Various experimental approaches involving RNAi-mediated knockdown, conditional gene deletion or small molecule inhibitors indicate a positive role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-?B p65 and its deacetylation at various lysines. NF-?B p65-deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-?B p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently observed for HDAC inhibitors in (pre)clinical use.

Published
2012
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28. HDAC1,2 inhibition impairs EZH2- and BBAP- mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma

Author

Johnson, Danielle P., primary, Spitz, Gabriella S., additional, Tharkar, Shweta, additional, Quayle, Steven N., additional, Shearstone, Jeffrey R., additional, Jones, Simon, additional, McDowell, Maria E., additional, Wellman, Hannah, additional, Tyler, Jessica K., additional, Cairns, Bradley R., additional, Chandrasekharan, Mahesh B., additional, and Bhaskara, Srividya, additional

Published
2014
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29. Histone deacetylase inhibitor treatment induces ‘BRCAness’ and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells

Author

Ha, Kyungsoo, primary, Fiskus, Warren, additional, Choi, Dong Soon, additional, Bhaskara, Srividya, additional, Cerchietti, Leandro, additional, Devaraj, Santhana G. T., additional, Shah, Bhavin, additional, Sharma, Sunil, additional, Chang, Jenny C., additional, Melnick, Ari M., additional, Hiebert, Scott, additional, and Bhalla, Kapil N., additional

Published
2014
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31. A Hybrid Mechanism of Action for BCL6 in B Cells Defined by Formation of Functionally Distinct Complexes at Enhancers and Promoters

Author

Hatzi, Katerina, primary, Jiang, Yanwen, additional, Huang, Chuanxin, additional, Garrett-Bakelman, Francine, additional, Gearhart, Micah D., additional, Giannopoulou, Eugenia G., additional, Zumbo, Paul, additional, Kirouac, Kevin, additional, Bhaskara, Srividya, additional, Polo, Jose M., additional, Kormaksson, Matthias, additional, MacKerell, Alexander D., additional, Xue, Fengtian, additional, Mason, Christopher E., additional, Hiebert, Scott W., additional, Prive, Gilbert G., additional, Cerchietti, Leandro, additional, Bardwell, Vivian J., additional, Elemento, Olivier, additional, and Melnick, Ari, additional

Published
2013
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32. Inhibition of Histone Deacetylase 3 Causes Replication Stress in Cutaneous T Cell Lymphoma

Author

Wells, Christina E., primary, Bhaskara, Srividya, additional, Stengel, Kristy R., additional, Zhao, Yue, additional, Sirbu, Bianca, additional, Chagot, Benjamin, additional, Cortez, David, additional, Khabele, Dineo, additional, Chazin, Walter J., additional, Cooper, Andrew, additional, Jacques, Vincent, additional, Rusche, James, additional, Eischen, Christine M., additional, McGirt, Laura Y., additional, and Hiebert, Scott W., additional

Published
2013
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33. Abstract B14: A biochemical basis for toggling enhancers from the active to poised state in B-cells

Author

Chatzi, Katerina, primary, Jiang, Yanwen, additional, Huang, Chuanxin, additional, Zumbo, Paul, additional, Bhaskara, Srividya, additional, MacKerell, Alexander D., additional, Xue, Fengtian, additional, Mason, Christopher E., additional, Hiebert, Scott W., additional, Cerchietti, Leandro, additional, Bardwell, Vivian J., additional, Elemento, Olivier, additional, and Ari, Melnick, additional

Published
2013
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34. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB

Author

Ziesché, Elisabeth, primary, Kettner-Buhrow, Daniela, additional, Weber, Axel, additional, Wittwer, Tobias, additional, Jurida, Liane, additional, Soelch, Johanna, additional, Müller, Helmut, additional, Newel, Doris, additional, Kronich, Petra, additional, Schneider, Heike, additional, Dittrich-Breiholz, Oliver, additional, Bhaskara, Srividya, additional, Hiebert, Scott W., additional, Hottiger, Michael O., additional, Li, Haiying, additional, Burstein, Ezra, additional, Schmitz, M. Lienhard, additional, and Kracht, Michael, additional

Published
2012
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45. Inhibition of Histone Deacetylase 3 Causes Replication Stress in Cutaneous T Cell Lymphoma.

Author

Wells, Christina E., Bhaskara, Srividya, Stengel, Kristy R., Zhao, Yue, Sirbu, Bianca, Chagot, Benjamin, Cortez, David, Khabele, Dineo, Chazin, Walter J., Cooper, Andrew, Jacques, Vincent, Rusche, James, Eischen, Christine M., McGirt, Laura Y., and Hiebert, Scott W.

Subjects
*HISTONE deacetylase inhibitors, *PHYSIOLOGICAL stress, *DNA repair, *DNA replication, *GENETIC transcription, *GENETIC regulation, *DEPSIPEPTIDES, *CANCER cell proteins
Abstract

Given the fundamental roles of histone deacetylases (HDACs) in the regulation of DNA repair, replication, transcription and chromatin structure, it is fitting that therapies targeting HDAC activities are now being explored as anti-cancer agents. In fact, two histone deacetylase inhibitors (HDIs), SAHA and Depsipeptide, are FDA approved for single-agent treatment of refractory cutaneous T cell lymphoma (CTCL). An important target of these HDIs, histone deacetylase 3 (HDAC3), regulates processes such as DNA repair, metabolism, and tumorigenesis through the regulation of chromatin structure and gene expression. Here we show that HDAC3 inhibition using a first in class selective inhibitor, RGFP966, resulted in decreased cell growth in CTCL cell lines due to increased apoptosis that was associated with DNA damage and impaired S phase progression. Through isolation of proteins on nascent DNA (iPOND), we found that HDAC3 was associated with chromatin and is present at and around DNA replication forks. DNA fiber labeling analysis showed that inhibition of HDAC3 resulted in a significant reduction in DNA replication fork velocity within the first hour of drug treatment. These results suggest that selective inhibition of HDAC3 could be useful in treatment of CTCL by disrupting DNA replication of the rapidly cycling tumor cells, ultimately leading to cell death. [ABSTRACT FROM AUTHOR]

Published
2013
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46. The neural stem-cell marker CD24is specifically upregulated in IDH-mutant glioma

Author

Tiburcio, Patricia D.B., Locke, Mary C., Bhaskara, Srividya, Chandrasekharan, Mahesh B., and Huang, L. Eric

Abstract

Malignant gliomas have disproportionally high morbidity and mortality. Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, resulting in predominantly arginine to histidine substitution at codon 132. Because IDH1R132Hrequires a wild-type allele to produce (D)-2-hydroxyglutarate for epigenetic reprogramming, loss of IDH1R132Hheterozygosity is associated with glioma progression in an IDH1-wildtype-like phenotype. Although previous studies have reported that transgenic IDH1R132Hinduces the expression of nestin—a neural stem-cell marker, the underlying mechanism remains unclear. Furthermore, this finding seems at odds with better outcome of IDH1R132Hglioma because of a negative association of nestin with overall survival.

Published
2020
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47. Molecular mechanism of caffeine-induced expression of two cytochrome P450 genes, <em>Cyp6a2</em> and <em>Cyp6a8</em>, in <em>Drosophila melanogaster</em>

Author

Bhaskara, Srividya

Subjects
Biochemistry, Biophysics, and Structural Biology
Abstract

Cytochrome P450 monooxygenases or CYPs comprise a large family of enzymes that are found in all classes of living organisms, from bacteria to man. These enzymes are involved in the metabolism of many endogenous and xenobiotic (foreign) compounds. In insects, CYPs confer resistance to various insecticides, and resistance-associated overexpression of multiple CYP genes in resistant insects is a common phenomenon. In Drosophila, multiple Cyp genes including Cyp6a2 and Cyp6a8 show higher level of expression in resistant strains than in the susceptible ones. To date, molecular basis of CYP gene overexpression has not been examined in detail. Barbiturate compounds such as phenobarbital and barbital induce both these genes. An unpublished observation from our laboratory showed that Cyp6a2 as well as Cyp6a8 are induced by over-the-counter caffeine tablet, Vivarin. In the present study, I used pure caffeine as a tool to better understand the mechanism of Cyp6a2 and Cyp6a8 gene regulation in Drosophila. The specific objectives of this project has been to (1) map the upstream DNA of both genes for the sequences responsible for caffeine-induction; (2) examine whether adenosine receptors and/or cAMP-specific phosphodiesterase (cPDE) are involved in transduction of caffeine signal to induce the two Cyp6 genes; and (3) investigate whether Drosophila AP-l transcription factors (D-JUN and D-FOS) playa role in caffeine induction of Cyp6a8 gene. For these objectives, several Cyp-luc reporter plasmids carrying firefly lueiferase (luc) reporter gene under the control of different regions of Cyp6a8 and Cyp6a2 upstream DNAs were constructed to transfect Drosophila embryonic cells, Schneider line 2 (SL-2). Two transgenic reporter strains carrying firefly lueiferase (luc) reporter gene under the control of O.8-kb or 0.2-kb upstream DNA of Cyp6a8 gene were also used to study the mechanism of caffeine induction in vivo. Results of Northern blot analysis showed that caffeine induces endogenous Cyp6a2 and Cyp6a8 genes at the steady-state mRNA levels both in reporter transgenic and wild-type flies. Transfection experiments with SL-2 cells showed that -983/-1 and 7611-11 upstream DNAs of Cyp6a2 and Cyp6a8, respectively, have sequences for caffeine-induced expression. Further transfection experiments with reporter plasmids carrying luc reporter gene attached to truncated upstream DNAs of Cyp6a2 and Cyp6a8 genes showed that the regions between -265/-129 of Cyp6a2 and -199/-109 of Cyp6a8 have sequences that confer caffeine-induced expression. However, the level of both constitutive and induced expression was highest with -981/-1 DNA of Cyp6a2and -761111 DNA of Cyp6a8genes. Sequence analysis identified several putative binding sites for Activator Protein -1 (AP-l) and cyclic AMP response element CRE binding protein. (CREB) motifs in the upstream DNA of both genes. Moreover, when the four core bases of the single AP-l site present in the -109/-11 DNA of Cyp6a8 were mutated, constitutive expression decreased by 8-fold, suggesting the positive role of AP-l in Cyp6a8 gene expression. To examine whether caffeine signaling is mediated via adenosine receptor (AdoR) and/or via cPDE inhibition, SL-2 cells transfected with Cyp6a2 and Cyp6a8 reporter constructs were treated with AdoR agonists or with antagonists or with cPDE inhibitors. The Cyp6a8-luc reporter transgenic lines were also treated with these chemicals. The results showed that caffeine signaling is mediated by PDE inhibition and via increase in the intracellular cAMP level. Indeed, treatment with dibutyryl cAMP induces Cyp6a2 as well as Cyp6a8 promoters. Since induction of cAMP pathway is known to upregulate AP-I transcription factors, effect of overexpression of Drosophila D-FOS and (or) DJUN (components of AP-I) on Cyp6a8 promoter activity in SL-2 cells was examined. Surprisingly, activity of Cyp6a8-1uc reporter construct was inhibited when D-FOS or DJUN proteins were overexpressed, suggesting that AP-I proteins are inhibitory for Cyp6 gene expression. In contrast, the Cyp6a8 promoter activity was upregulated, when cells were transfected with anti-D-JUN plasmid or when cells transfected with D-JUN or DFOS sense construct were treated with caffeine. When relation between caffeine and the two AP-I proteins was examined, it was found that caffeine treatment significantly lowers the D-JUN protein level both in SL-2 cells as well as in adult flies. Reporter gene assays and Northern blot analysis showed that caffeine treatment has no effect on the transcriptional activity of the D-jun and D-fos genes. Taken together, it might be concluded that caffeine induction of Cyp6a2 and Cyp6a8 genes is mediated via degradation of D-JUN that acts as a repressor for the promoter of Cyp6a8. Induction of the cAMP pathway and subsequent phosphorylation of the AP-l proteins may relieve the AP-l mediated-repression by promoting the degradation of these proteins. Further investigation is required to resolve these possibilities.

Published
2005

48. Interaction of the Jhd2 Histone H3 Lys-4 Demethylase with Chromatin Is Controlled by Histone H2A Surfaces and Restricted by H2B Ubiquitination.

Author

Fu Huang, Ramakrishnan, Saravanan, Pokhrel, Srijana, Pflueger, Christian, Parnell, Timothy J., Kasten, Margaret M., Currie, Simon L., Bhachech, Niraja, Masami Horikoshi, Graves, Barbara J., Cairns, Bradley R., Bhaskara, Srividya, and Chandrasekharan, Mahesh B.

Subjects
*HISTONES, *METHYLATION, *METHYLTRANSFERASES, *DEMETHYLASE, *CHROMATIN, *UBIQUITINATION
Abstract

Histone H3 lysine 4 (H3K4) methylation is a dynamic modification. In budding yeast, H3K4 methylation is catalyzed by the Set1-COMPASS methyltransferase complex and is removed by Jhd2, a JMJC domain family demethylase. The catalytic JmjC and JmjN domains of Jhd2 have the ability to remove all three degrees (mono-, di-, and tri-) of H3K4 methylation. Jhd2 also contains a plant homeodomain (PHD) finger required for its chromatin association and H3K4 demethylase functions. The Jhd2 PHD finger associates with chromatin independent of H3K4 methylation and the H3 N-terminal tail. Therefore, how Jhd2 associates with chromatin to perform H3K4 demethylation has remained unknown. We report a novel interaction between the Jhd2 PHD finger and histone H2A. Two residues in H2A (Phe-26 and Glu-57) serve as a binding site for Jhd2 in vitro and mediate its chromatin association and H3K4 demethylase functions in vivo. Using RNA sequencing, we have identified the functional target genes for Jhd2 and theH2APhe-26 and Glu-57 residues.Wedemonstrate thatH2APhe-26 and Glu-57 residues control chromatin association and H3K4 demethylase functions of Jhd2 during positive or negative regulation of transcription at target genes. Importantly, we show that H2B Lys-123 ubiquitination blocks Jhd2 from accessing its binding site on chromatin, and thereby, we have uncovered a second mechanism by which H2B ubiquitination contributes to the trans-histone regulation of H3K4 methylation. Overall, our study provides novel insights into the chromatin binding dynamics and H3K4 demethylase functions of Jhd2. [ABSTRACT FROM AUTHOR]

Published
2015
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49. Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug.

Author

Girard PM, Berthault N, Kozlac M, Ferreira S, Jdey W, Bhaskara S, Alekseev S, Thomas F, and Dutreix M

Abstract

It is increasingly suggested that ecological and evolutionary sciences could inspire novel therapies against cancer but medical evidence of this remains scarce at the moment. The Achilles heel of conventional and targeted anticancer treatments is intrinsic or acquired resistance following Darwinian selection; that is, treatment toxicity places the surviving cells under intense evolutionary selective pressure to develop resistance. Here, we review a set of data that demonstrate that Darwinian principles derived from the "smoke detector" principle can instead drive the evolution of malignant cells toward a different trajectory. Specifically, long-term exposure of cancer cells to a strong alarm signal, generated by the DNA repair inhibitor AsiDNA, induces a stable new state characterized by a down-regulation of the targeted pathways and does not generate resistant clones. This property is due to the original mechanism of action of AsiDNA, which acts by overactivating a "false" signaling of DNA damage through DNA-PK and PARP enzymes, and is not observed with classical DNA repair inhibitors such as the PARP inhibitors. Long-term treatment with AsiDNA induces a new "alarm down" state in the tumor cells with decrease in NAD level and reactiveness to it. These results suggest that agonist drugs such as AsiDNA could promote a state-dependent tumor cell evolution by lowering their ability to respond to high "danger" signal. This analysis provides a compelling argument that evolutionary ecology could help drug design development in overcoming fundamental limitation of novel therapies against cancer due to the modification of the targeted tumor cell population during treatment., Competing Interests: The authors have submitted patents for the AsiDNA technology., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Published
2020
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50. HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma.

Author

Johnson DP, Spitz GS, Tharkar S, Quayle SN, Shearstone JR, Jones S, McDowell ME, Wellman H, Tyler JK, Cairns BR, Chandrasekharan MB, and Bhaskara S

Subjects
Adult, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, HeLa Cells, Histone Deacetylase 1 genetics, Histone Deacetylase 1 metabolism, Histone Deacetylase 2 genetics, Histone Deacetylase 2 metabolism, Humans, Lymphoma, Large B-Cell, Diffuse metabolism, Male, Polycomb Repressive Complex 2 genetics, Transfection, Ubiquitin-Protein Ligases genetics, DNA Repair, Histone Deacetylase 1 antagonists & inhibitors, Histone Deacetylase 2 antagonists & inhibitors, Histone Deacetylase Inhibitors pharmacology, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse genetics, Polycomb Repressive Complex 2 metabolism, Ubiquitin-Protein Ligases metabolism
Abstract

Gain-of-function mutations in the catalytic site of EZH2 (Enhancer of Zeste Homologue 2), is observed in about 22% of diffuse large B-cell lymphoma (DLBCL) cases. Here we show that selective inhibition of histone deacetylase 1,2 (HDAC1,2) activity using a small molecule inhibitor causes cytotoxic or cytostatic effects in EZH2 gain-of-function mutant (EZH2GOF) DLBCL cells. Our results show that blocking the activity of HDAC1,2 increases global H3K27ac without causing a concomitant global decrease in H3K27me3 levels. Our data shows that inhibition of HDAC1,2 is sufficient to decrease H3K27me3 present at DSBs, decrease DSB repair and activate the DNA damage response in these cells. In addition to increased H3K27me3, we found that the EZH2GOF DLBCL cells overexpress another chemotherapy resistance factor - B-lymphoma and BAL-associated protein (BBAP). BBAP monoubiquitinates histone H4K91, a residue that is also subjected to acetylation. Our results show that selective inhibition of HDAC1,2 increases H4K91ac, decreases BBAP-mediated H4K91 monoubiquitination, impairs BBAP-dependent DSB repair and sensitizes the refractory EZH2GOF DLBCL cells to treatment with doxorubicin, a chemotherapy agent. Hence, selective HDAC1,2 inhibition provides a novel DNA repair mechanism-based therapeutic approach as it can overcome both EZH2- and BBAP-mediated DSB repair in the EZH2GOF DLBCL cells.

Published
2015
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