EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma

Autor: Chao-Qun Liu, Jing Chen, Xing-Juan Yu, Yaojun Zhang, Li-Lian Jin, Zhong-Guo Zhou, Limin Zheng, Ya-Ming Meng, Jing Xu, Yongchun Wang, Gang Xiao
Rok vydání: 2019
Předmět:
PD-L1
Male
0301 basic medicine
Jumonji Domain-Containing Histone Demethylases
Cancer Research
Carcinoma
Hepatocellular
Immunology
macromolecular substances
lcsh:RC254-282
B7-H1 Antigen
Interferon-gamma
03 medical and health sciences
0302 clinical medicine
Cell Line
Tumor
Humans
Immunology and Allergy
Enhancer of Zeste Homolog 2 Protein
EZH2
STAT1
Epigenetics
Promoter Regions
Genetic
Enhancer
Transcription factor
Pharmacology
biology
Liver Neoplasms
Promoter
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gene Expression Regulation
Neoplastic
030104 developmental biology
IRF1
Oncology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Molecular Medicine
Female
Immunotherapy
Chromatin immunoprecipitation
Research Article
Interferon Regulatory Factor-1
Zdroj: Journal for Immunotherapy of Cancer
Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-15 (2019)
ISSN: 2051-1426
DOI: 10.1186/s40425-019-0784-9
Popis: 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.
Databáze: OpenAIRE
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