2. Academic Validation
  3. EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma

EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma

  • J Immunother Cancer. 2019 Nov 14;7(1):300. doi: 10.1186/s40425-019-0784-9.
Gang Xiao 1 2 3,  Li-Lian Jin 4,  Chao-Qun Liu 1 2 3,  Yong-Chun Wang 1,  Ya-Ming Meng 3 4,  Zhong-Guo Zhou 5,  Jing Chen 1,  Xing-Juan Yu 1,  Yao-Jun Zhang 5,  Jing Xu 6,  Limin Zheng 7 8
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
  • 2 Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.
  • 3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
  • 4 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China.
  • 5 Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
  • 6 Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China. xujing@sysucc.org.cn.
  • 7 Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China. zhenglm@mail.sysu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China. zhenglm@mail.sysu.edu.cn.
PMID: 31727135 DOI: 10.1186/s40425-019-0784-9
Abstract

Background: Accumulating studies suggest that targeting epigenetic modifications could improve the efficacy of tumor immunotherapy; however, the mechanisms underlying this phenomenon remain largely unknown. Here, we investigated the ability of the epigenetic modifier, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), to regulate the expression of immune checkpoint inhibitor, programmed death-1 ligand 1 (PD-L1) in hepatocellular carcinoma (HCC).

Methods: Immunohistochemistry and multiplex immunofluorescence staining were performed to analyze the expression and correlation of EZH2 and PD-L1 in HCC tissues. Immunoblotting, quantitative Real-Time PCR, flow cytometry, chromatin immunoprecipitation, and dual-luciferase reporter gene assays were performed to evaluate the regulatory roles of EZH2 on PD-L1 expression.

Results: In vitro cell experiments revealed that EZH2 negatively regulated the PD-L1 expression of hepatoma cell lines in IFNγ-dependent manner. Mechanistic studies demonstrated that EZH2 could suppress PD-L1 expression by upregulating the H3K27me3 levels on the promoters of CD274 (encoding PD-L1) and interferon regulatory factor 1 (IRF1), an essential transcription factor for PD-L1 expression, without affecting the activation of the IFNγ-signal transducer and activator of transcription 1 (STAT1) pathway. Clinical samples from HCC patients with immune-activated microenvironments showed negative correlations between EZH2 and PD-L1 expression in hepatoma cells. Multivariate COX analysis demonstrated that the combination of EZH2 and PD-L1 was an independent prognostic factor for both OS and RFS for patients with HCC.

Conclusions: The epigenetic modificator EZH2 can suppress the expression of immune checkpoint inhibitor PD-L1 by directly upregulating the promoter H3K27me3 levels of CD274 and IRF1 in hepatoma cells, and might serve as a potential therapeutic target for combination of immunotherapy for immune-activated HCC.

Keywords

EZH2; Epigenetics; Immunotherapy; PD-L1.

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