Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma

Yuanjun Lu, Yau-Tuen Chan, Hor-Yue Tan, Cheng Zhang, Wei Guo, Yu Xu, Rakesh Sharma, Zhe-Sheng Chen, Yi-Chao Zheng, Ning Wang*, Yibin Feng

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

83 Citations (Scopus)

Abstract

Background: Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified.

Methods: The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets.

Results: We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response.

Conclusion: Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.

Original languageEnglish
Article number3
Number of pages17
JournalJournal of Experimental and Clinical Cancer Research
Volume41
DOIs
Publication statusPublished - 3 Jan 2022

Scopus Subject Areas

  • Oncology
  • Cancer Research

User-Defined Keywords

  • ACSL4
  • ETS1
  • Ferroptosis
  • Hepatocellular carcinoma
  • MiR-23a-3p
  • Sorafenib resistance
  • Humans
  • Drug Resistance, Neoplasm
  • Coenzyme A Ligases/metabolism
  • Sorafenib/pharmacology
  • Carcinoma, Hepatocellular/drug therapy
  • Antineoplastic Agents/pharmacology
  • Animals
  • Ferroptosis/genetics
  • Liver Neoplasms/drug therapy
  • Mice, Inbred NOD
  • Epigenesis, Genetic/genetics

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