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Supplemental Table S2 from The Methyltransferases METTL7A and METTL7B Confer Resistance to Thiol-Based Histone Deacetylase Inhibitors

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posted on 2024-04-02, 07:23 authored by Robert W. Robey, Christina M. Fitzsimmons, Wilfried M. Guiblet, William J.E. Frye, José M. González Dalmasy, Li Wang, Drake A. Russell, Lyn M. Huff, Andrew J. Perciaccante, Fatima Ali-Rahmani, Crystal C. Lipsey, Heidi M. Wade, Allison V. Mitchell, Siddhardha S. Maligireddy, David Terrero, Donna Butcher, Elijah F. Edmondson, Lisa M. Jenkins, Tatiana Nikitina, Victor B. Zhurkin, Amit K. Tiwari, Anthony D. Piscopio, Rheem A. Totah, Susan E. Bates, H. Efsun Arda, Michael M. Gottesman, Pedro J. Batista

Supplemental Table S2 contains information about the cross-resistance profile of MCF7 DpVp300 cells for multiple drugs

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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American Cancer Society (ACS)

U.S. Department of Defense (DOD)

National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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National Heart, Lung, and Blood Institute (NHLBI)

History

ARTICLE 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.

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    Molecular Cancer Therapeutics

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    Keywords

    Drug ResistanceNovel mechanismsEpigeneticsHistone ModificationMetabolismSmall Molecule AgentsEpigenetic-targeted agentsHDAC & methyltransferase inhibitors

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