1. Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation
- Author
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Marchal, Claire, de Dieuleveult, Maud, Saint-Ruf, Claude, Guinot, Nadège, Ferry, Laure, Olalla Saad, Sara T., Lazarini, Mariana, Defossez, Pierre-Antoine, Miotto, Benoit, Miotto, Benoit, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hematology and Blood Transfusion Center [Campinas, Brazil], University of Campinas/Hemocentro-Unicamp [Campinas, Brazil] -Instituto Nacional de Ciência e Tecnologia do Sangue [Campinas, Brazil], Department of Biological Sciences [Diadema, Brazil], Federal University of Sao Paulo (Unifesp), This work was supported by grants from Electricité de France (#123518) and Ligue Contre le Cancer - Comité de Paris (RS11/75-81, RS12/75/95-21, RS13/75-59). Work of B.M. is supported by FP7 Marie Curie action (PIRG07-GA-2010-268448), Fondation pour la Recherche Médicale (AJE20151234749), Institut National du Cancer-Plan Cancer (ASC15018KSA) and Institut Cochin (POC2016). PAD was supported by grants from Fondation ARC (Projet 2014), Ligue contre le cancer – Comité de Paris, and Institut National du Cancer (PLBIO 2015_1-PLBIO-01-DRA-1). ML and STOS are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and Instituto Nacional de Ciência e Tecnologia do Sangue [Campinas, Brazil]-University of Campinas/Hemocentro-Unicamp [Campinas, Brazil]
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[SDV] Life Sciences [q-bio] ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,[SDV]Life Sciences [q-bio] ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,1234567890() ,lcsh:RC254-282 ,Article - Abstract
International audience; DNA methyltransferase inhibitor (DNMTi) treatments have been used for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and have shown promising beneficial effects in some other types of cancers. Here, we demonstrate that the transcriptional repressor ZBTB38 is a critical regulator of the cellular response to DNMTi. Treatments with 5-azacytidine, or its derivatives decitabine and zebularine, lead to down-regulation of ZBTB38 protein expression in cancer cells, in parallel with cellular damage. The depletion of ZBTB38 by RNA interference enhances the toxicity of DNMTi in cell lines from leukemia and from various solid tumor types. Further we observed that inactivation of ZBTB38 causes the up-regulation of CDKN1C mRNA, a previously described indirect target of DNMTi. We show that CDKN1C is a key actor of DNMTi toxicity in cells lacking ZBTB38. Finally, in patients with MDS a high level of CDKN1C mRNA expression before treatment correlates with a better clinical response to a drug regimen combining 5-azacytidine and histone deacetylase inhibitors. Collectively, our results suggest that the ZBTB38 protein is a target of DNMTi and that its depletion potentiates the toxicity of DNMT inhibitors in cancer cells, providing new opportunities to enhance the response to DNMT inhibitor therapies in patients with MDS and other cancers.
- Published
- 2018
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