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Enhancer of zeste 2 polycomb repressive complex 2 subunit promotes sorafenib resistance of hepatocellular carcinoma though insulin-like growth factor 1 receptor

Hu, Jinga; Zhang, Jingc; Sun, Feifeia; Qi, Meib; Su, Pengb; Liu, Huia; Gao, Lina; Jiao, Menga; Wu, Zhena; Xiang, Leib; Han, Boa,b

doi: 10.1097/CAD.0000000000000746
Preclinical Reports
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Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is the core component of polycomb repressive complex 2 and is overexpressed in several types of solid malignancies. It has been reported that EZH2 contributes to sorafenib resistance of hepatocellular carcinoma (HCC). However, its underlying molecular mechanisms remain unknown. In this study, we demonstrated that EZH2 induced sorafenib resistance of HCC cells in vitro. Mechanistically, EZH2 was a potent regulator of insulin-like growth factor 1 receptor (IGF1R) and EZH2-modulated IGF1R expression by directly transcriptionally repressing a set of microRNAs (miRNAs) including miR-101, miR-122, miR-125b, and miR-139. These miRNAs were required for EZH2-mediated sorafenib resistance by promoting IGF1R expression. Surprisingly, IGF1R inhibitors significantly reversed EZH2-induced sorafenib resistance. Collectively, we proposed a novel model for an EZH2 – miRNAs – IGF1R regulatory axis, which might provide insights into how EZH2 contributes to sorafenib resistance in HCC.

aKey Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University QiLu Medical College

bDepartment of Pathology, Shandong University Qilu Hospital

cDepartment of Pharmacy, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, China

Received 31 August 2018 Revised form accepted 22 December 2018

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Correspondence to Bo Han, MD, PhD, Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University QiLu Medical College, Jinan 250012, China Tel/fax: + 86 531 8216 9225; e-mail: boh@sdu.edu.cn

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