5-methylcytosine methylation of MALAT1 promotes resistance to sorafenib in hepatocellular carcinoma through ELAVL1/SLC7A11-mediated ferroptosis

Drug Resist Updat. 2025 Jan:78:101181. doi: 10.1016/j.drup.2024.101181. Epub 2024 Dec 4.

Abstract

Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) play a crucial role in sorafenib resistance in hepatocellular carcinoma (HCC), and lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a dysregulated lncRNA in sorafenib-resistant HCC cells. However, the underlying regulatory mechanisms of MALAT1 in sorafenib-resistant HCC cells remain unclear. In the present study, we demonstrated that 5-methylcytosine (m5C) methylation catalyzed by NSUN2 and ALYREF contributed to the RNA stability and upregulation of MALAT1. The NSUN2/ALYREF/MALAT1 signaling axis was activated in sorafenib-resistant cells, and the upregulation of MALAT1 inhibited sorafenib-induced ferroptosis to drive sorafenib resistance. Mechanistically, MALAT1 maintained the mRNA stability of SLC7A11 by directly binding to ELAVL1 and stimulating its cytoplasmic translocation. Furthermore, we explored a new synergetic strategy for the treatment of HCC by combining MALAT1 inhibitor MALAT1-IN1 with sorafenib. The results demonstrated that MALAT1-IN1 significantly enhanced sorafenib efficacy for the treatment of HCC both in vitro and in vivo. Collectively, our work brings new insights into the epigenetic mechanisms of sorafenib resistance and offers an alternative therapeutic strategy targeting ferroptosis for sorafenib-resistant HCC patients.

Keywords: Ferroptosis; Hepatocellular carcinoma; MALAT1; SLC7A11; Sorafenib resistance; m(5)C methylation.

MeSH terms

  • 5-Methylcytosine* / analogs & derivatives
  • 5-Methylcytosine* / metabolism
  • Amino Acid Transport System y+* / genetics
  • Amino Acid Transport System y+* / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • ELAV-Like Protein 1* / genetics
  • ELAV-Like Protein 1* / metabolism
  • Ferroptosis* / drug effects
  • Ferroptosis* / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Methylation / drug effects
  • Mice
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Sorafenib* / pharmacology
  • Sorafenib* / therapeutic use

Substances

  • Sorafenib
  • RNA, Long Noncoding
  • MALAT1 long non-coding RNA, human
  • SLC7A11 protein, human
  • 5-Methylcytosine
  • ELAV-Like Protein 1
  • Amino Acid Transport System y+
  • ELAVL1 protein, human
  • Antineoplastic Agents