PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer

Nat Commun. 2023 Apr 6;14(1):1932. doi: 10.1038/s41467-023-37542-5.

Abstract

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Cell Line, Tumor
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Methylation
  • Oxaliplatin / pharmacology
  • Oxaliplatin / therapeutic use
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism

Substances

  • Oxaliplatin
  • PRMT3 protein, human
  • Protein-Arginine N-Methyltransferases
  • IGF2BP1 protein, human