{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Robey RW"],"funding":["National Heart, Lung, and Blood Institute (NHLBI)","Intramural NIH HHS","NHLBI NIH HHS","National Heart, Lung, and Blood Institute","U.S. Department of Defense (DOD)","National Institute of General Medical Sciences","National Cancer Institute (NCI)","American Cancer Society","U.S. Department of Defense","National Cancer Institute","American Cancer Society (ACS)","NIGMS NIH HHS","National Institute of General Medical Sciences (NIGMS)"],"pagination":["464-477"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11223745"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["23(4)"],"pubmed_abstract":["Histone deacetylase inhibitors (HDACi) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi romidepsin in vitro, yet increased ABCB1 expression has not been associated with resistance in patients, suggesting that other mechanisms of resistance arise in the clinic. To identify alternative mechanisms of resistance to romidepsin, we selected MCF-7 breast cancer cells with romidepsin in the presence of the P-gp inhibitor verapamil to reduce the likelihood of P-gp-mediated resistance. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidepsin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA-sequencing analysis revealed upregulation of the mRNA coding for the putative methyltransferase, METTL7A, whose paralog, METTL7B, was previously shown to methylate thiol groups on hydrogen sulfide and captopril. As romidepsin has a thiol as the zinc-binding moiety, we hypothesized that METTL7A could inactivate romidepsin and other thiol-based HDACis via methylation of the thiol group. We demonstrate that expression of METTL7A or METTL7B confers resistance to thiol-based HDACis and that both enzymes are capable of methylating thiol-containing HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol."],"journal":["Molecular cancer therapeutics"],"pubmed_title":["The Methyltransferases METTL7A and METTL7B Confer Resistance to Thiol-Based Histone Deacetylase Inhibitors."],"pmcid":["PMC11223745"],"funding_grant_id":["R01 HL146603","Grant T32-GM007750","ZIA BC011766","T32 GM007750","PF-19-157-01-RMC","1W81XWH-21-1-0053","Grant R01-HL146603"],"pubmed_authors":["Totah RA","Piscopio AD","Russell DA","Lipsey CC","Terrero D","Wang L","Guiblet WM","Frye WJE","Gottesman MM","Robey RW","Maligireddy SS","Perciaccante AJ","Ali-Rahmani F","Edmondson EF","Arda HE","Tiwari AK","Huff LM","Wade HM","Mitchell AV","Jenkins LM","Butcher D","Batista PJ","Bates SE","Gonzalez Dalmasy JM","Fitzsimmons CM","Zhurkin VB","Nikitina T"],"additional_accession":[]},"is_claimable":false,"name":"The Methyltransferases METTL7A and METTL7B Confer Resistance to Thiol-Based Histone Deacetylase Inhibitors.","description":"Histone deacetylase inhibitors (HDACi) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi romidepsin in vitro, yet increased ABCB1 expression has not been associated with resistance in patients, suggesting that other mechanisms of resistance arise in the clinic. To identify alternative mechanisms of resistance to romidepsin, we selected MCF-7 breast cancer cells with romidepsin in the presence of the P-gp inhibitor verapamil to reduce the likelihood of P-gp-mediated resistance. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidepsin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA-sequencing analysis revealed upregulation of the mRNA coding for the putative methyltransferase, METTL7A, whose paralog, METTL7B, was previously shown to methylate thiol groups on hydrogen sulfide and captopril. As romidepsin has a thiol as the zinc-binding moiety, we hypothesized that METTL7A could inactivate romidepsin and other thiol-based HDACis via methylation of the thiol group. We demonstrate that expression of METTL7A or METTL7B confers resistance to thiol-based HDACis and that both enzymes are capable of methylating thiol-containing HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2025-04-04T12:21:38.026Z","creation":"2025-04-04T12:21:38.026Z"},"accession":"S-EPMC11223745","cross_references":{"pubmed":["38151817"],"doi":["10.1158/1535-7163.MCT-23-0144","10.1158/1535-7163.mct-23-0144"]}}