2. Academic Validation
  3. MAPK13 stabilization via m6A mRNA modification limits anti-cancer efficacy of rapamycin

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

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: ginalee@uci.edu.
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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