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

Robey, R. W.; Fitzsimmons, C. M.; Guiblet, W. M.; Frye, W. J. E.; Gonzalez Dalmasy, J.; Wang, L.; Huff, L. M.; Ali-Rahmani, F.; Lipsey, C. C.; Wade, H. M.; Mitchell, A. V.; Maligireddy, S. S.; Jenkins, L. M.; Nikitina, T.; Zhurkin, V. B.; Piscopio, A. D.; Bates, S. E.; Arda, H. E.; Gottesman, M. M.; Batista, P. J.

doi:10.1101/2022.10.07.511310

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bioRxiv · 10.1101/2022.10.07.511310

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

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Abstract

Histone deacetylase inhibitors (HDACis) are part of a growing class of epigenetic therapies used for the treatment of cancer. While elevated levels of the efflux pump P-gp are associated with in vitro resistance to romidepsin, this mechanism does not translate to the clinic. We developed a romidepsin-resistant cell line with a resistance mechanism independent of P-gp function that acts upstream of the deacetylation process. We found that expression of the methyltransferase METTL7A is necessary for resistance, and that expression of METTL7A in naive cells can drive resistance to thiol-containing HDACis. We demonstrate that METTL7A can methylate romidesin in vitro and that the ability of METTL7A to drive resistance to thiol-containing HDACis can be blocked by the methyltransferase inhibitor DCMB. Our data supports a model whereby exposure of cells to romidepsin selects for upregulation of the methyltransferase METTL7A, which in turn modifies the zinc-binding thiol, inactivating the drug.

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Robey, R. W., Fitzsimmons, C. M., Guiblet, W. M., Frye, W. J. E., Gonzalez Dalmasy, J., Wang, L., Huff, L. M., Ali-Rahmani, F., Lipsey, C. C., Wade, H. M., Mitchell, A. V., Maligireddy, S. S., Jenkins, L. M., Nikitina, T., Zhurkin, V. B., Piscopio, A. D., Bates, S. E., Arda, H. E., Gottesman, M. M., Batista, P. J.. 2022-10-07. The methyltransferases METTL7A and METTL7B confer resistance to thiol-based histone deacetylase inhibitors. https://doi.org/10.1101/2022.10.07.511310

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