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

  • J Biol Chem. 2023 Aug 18;105175. doi: 10.1016/j.jbc.2023.105175.
Joohwan Kim  1 ,  Yujin Chun  1 ,  Cuauhtemoc B Ramirez  2 ,  Lauren A Hoffner  1 ,  Sunhee Jung  3 ,  Ki-Hong Jang  1 ,  Varvara I Rubtsova  4 ,  Cholsoon Jang  3 ,  Gina Lee  5
Affiliations
  • 1. Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • 2. Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA, USA; Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • 3. Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • 4. Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA, USA; School of Biological Sciences, University of California Irvine, Irvine, CA, USA.
  • 5. Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA, USA. Electronic address: [email protected].
PMID: 37599001 DOI: 10.1016/j.jbc.2023.105175
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 (3'UTR) 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 (YTHDF2). Rapamycin blunts this process and stabilizes MAPK13. On the Other hand, genetic or pharmacological inhibition of MAPK13 enhances rapamycin's anti-cancer effects, which suggests that MAPK13 confers a pro-growth 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; Rapamycin; m(6)A; mTORC1; p38.
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