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

Journal of Experimental & Clinical Cancer Research

Hor-Yue Tan¹  Zhe-Sheng Chen²  Wei Guo³  Rakesh Sharma⁴  Cheng Zhang⁵  Yu Xu⁵  Yuanjun Lu⁵  Yau-Tuen Chan⁵  Ning Wang⁵  Yibin Feng⁵  Yi-Chao Zheng⁶ 

[1] Centre for Chinese Herbal Medicine Drug Development, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China;Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China;Proteomics and Metabolomics Core Facility, The University of Hong Kong, Hong Kong, China;School of Chinese Medicine, The University of Hong Kong, Hong Kong, China;School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China;

关键词: MiR-23a-3p;    Sorafenib resistance;    ETS1;    Ferroptosis;    ACSL4;    Hepatocellular carcinoma;   

DOI  :  10.1186/s13046-021-02208-x

来源: Springer

【 摘 要 】

BackgroundDrug 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.MethodsThe 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.ResultsWe 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.ConclusionOur 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.

【 授权许可】

CC BY