MAPK13 stabilization via m6A mRNA modification limits anticancer efficacy of rapamycin

Joohwan Kim; Yujin Chun; Cuauhtemoc B Ramirez; Lauren A Hoffner; Sunhee Jung; Ki-Hong Jang; Varvara I Rubtsova; Cholsoon Jang; Gina Lee

doi:10.1016/j.jbc.2023.105175

MAPK13 stabilization via m⁶A mRNA modification limits anticancer efficacy of rapamycin

J Biol Chem. 2023 Sep;299(9):105175. doi: 10.1016/j.jbc.2023.105175. Epub 2023 Aug 19.

Authors

Joohwan Kim¹, Yujin Chun¹, Cuauhtemoc B Ramirez², Lauren A Hoffner¹, Sunhee Jung³, Ki-Hong Jang¹, Varvara I Rubtsova⁴, Cholsoon Jang³, Gina Lee⁵

Affiliations

¹ Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, California, USA.
² Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, California, USA; Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, California, USA.
³ Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, California, USA.
⁴ Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, California, USA; School of Biological Sciences, University of California Irvine, Irvine, California, USA.
⁵ Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, California, USA. Electronic address: ginalee@uci.edu.

Abstract

N⁶-adenosine methylation (m⁶A) is the most abundant mRNA modification that controls gene expression through diverse mechanisms. Accordingly, m⁶A-dependent regulation of oncogenes and tumor suppressors contributes to tumor development. However, the role of m⁶A-mediated gene regulation upon drug treatment or resistance is poorly understood. Here, we report that m⁶A modification of mitogen-activated protein kinase 13 (MAPK13) mRNA determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1)-targeting agent rapamycin. mTORC1 induces m⁶A modification of MAPK13 mRNA at its 3' untranslated region through the methyltransferase-like 3 (METTL3)-METTL14-Wilms' tumor 1-associating protein(WTAP) methyltransferase complex, facilitating its mRNA degradation via an m⁶A reader protein YTH domain family protein 2. Rapamycin blunts this process and stabilizes MAPK13. On the other hand, genetic or pharmacological inhibition of MAPK13 enhances rapamycin's anticancer effects, which suggests that MAPK13 confers a progrowth signal upon rapamycin treatment, thereby limiting rapamycin efficacy. Together, our data indicate that rapamycin-mediated MAPK13 mRNA stabilization underlies drug resistance, and it should be considered as a promising therapeutic target to sensitize cancer cells to rapamycin.

Keywords: MAPK13; RNA modification; RNA stability; m(6)A; mTORC1; p38; rapamycin.

Abstract

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