The methyltransferases METTL7A and METTL7B confer resistance to thiol-based histone deacetylase inhibitors

Histone deacetylase inhibitors (HDACis) 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, solid tumors are resistant to these inhibitors. 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 chance of P-gp overexpression developing as a resistance mechanism. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidpesin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA sequencing analysis demonstrated upregulation of 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. Here we show that expression of METTL7A is necessary for thiol-based HDACi resistance in the MCF-7 DpVp300 cell line, and that expression of METTL7A or METTL7B in sensitive cells confers resistance to thiol-based HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol.