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bioRxiv · 10.1101/2022.08.05.502726

MAPK13 stabilization via m6A modification limits anti-cancer efficacy of rapamycin

Kim, J.·Chun, Y.·Ramirez, C. B.·Hoffner, L. A.·Jung, S.·Jang, K. H.·Rubtsova, V. I.·Jang, C.·Lee, G.
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Abstract

N6-adenosine methylation (m6A) is the most abundant mRNA modification that controls gene expression through diverse mechanisms. m6A-dependent regulation of oncogenes and tumor suppressors indeed contribute to tumor development. However, the role of m6A-mediated gene regulation after drug treatment or resistance is poorly understood. Here, we report that m6A modification of mitogen-activated protein kinase 13 (MAPK13) determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1)- targeting chemotherapeutic agent rapamycin. mTORC1 induces m6A modification of MAPK13 mRNA at its 3 untranslated region (3UTR) through methyltransferase-like 3 (METTL3)-METTL14-Wilms tumor 1-associating protein (WTAP) methyltransferase complex, thereby stimulating its mRNA degradation via an m6A reader protein YTH domain family protein 2 (YTHDF2). Rapamycin blunts this process and stabilizes MAPK13. Unexpectedly, MAPK13 silencing suppresses cell growth and enhances rapamycins anti-cancer effects, suggesting that MAPK13 is an oncogenic gene activated by rapamycin via a feedback regulation. Together, our data indicate that rapamycin-mediated MAPK13 mRNA stabilization may confer drug resistance, and it can thus be a therapeutic target to sensitize cancer cells to rapamycin.

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Kim, J., Chun, Y., Ramirez, C. B., Hoffner, L. A., Jung, S., Jang, K. H., Rubtsova, V. I., Jang, C., Lee, G.. 2022-08-06. MAPK13 stabilization via m6A modification limits anti-cancer efficacy of rapamycin. https://doi.org/10.1101/2022.08.05.502726

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