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

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

  • J Exp Clin Cancer Res. 2022 Jan 3;41(1):3. doi: 10.1186/s13046-021-02208-x.
Yuanjun Lu 1,  Yau-Tuen Chan 1,  Hor-Yue Tan 2,  Cheng Zhang 1,  Wei Guo 3,  Yu Xu 1,  Rakesh Sharma 4,  Zhe-Sheng Chen 5,  Yi-Chao Zheng 6,  Ning Wang 7,  Yibin Feng 8
Affiliations

Affiliations

  • 1 School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
  • 2 Centre for Chinese Herbal Medicine Drug Development, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
  • 3 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China.
  • 4 Proteomics and Metabolomics Core Facility, The University of Hong Kong, Hong Kong, China.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
  • 6 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
  • 7 School of Chinese Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
  • 8 School of Chinese Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
PMID: 34980204 DOI: 10.1186/s13046-021-02208-x
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.

Keywords

ACSL4; ETS1; Ferroptosis; Hepatocellular carcinoma; MiR-23a-3p; Sorafenib resistance.

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