Epigenetic silencing of ZIC4 contributes to cancer progression in hepatocellular carcinoma

Wenbiao Chen,Dongxin Tang,Donge Tang,Yong Dai

doi:10.1038/s41419-020-03109-1

Abstract

Inactivation of tumor suppressor gene played critical roles in the development and progression of human hepatocellular carcinoma (HCC). Zic family member 4 (ZIC4) is transcription factor and plays an important role in the developmental process. However, the expression and biological role of ZIC4 in HCC is poorly understood. Here, bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database revealed an aberrant hypermethylation of ZIC4 in HCC. ZIC4 is frequently hypermethylated in promoter region and down expressed in HCC cells and tissues. Functionally, ZIC4 inhibition facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, ZIC4 overexpression reduced proliferation and invasiveness of HCC cells. In addition, ZIC4 inhibition rescued the antitumor effect induced by enhancer of zeste homolog 2 (EZH2) knockdown or EZH2 inhibitor. Mechanistically, EZH2 knockdown or EZH2 inhibitor reduced the enrichment of EZH2 and H3K27me3 in ZIC4 promoter region and leading to the upregulation of ZIC4. Altogether, these data indicate that epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in HCC and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.

Highlights

Liver cancer is the fifth most critical malignant tumor and the second common leading cause of cancer-related death in males, according to statistics, there are about 782,500 people were diagnosed with liver cancer and 745,500 deaths in 2012 all over the world[1]
In this study, we explored the role of enhancer of zeste homolog 2 (EZH2) and Zic family member 4 (ZIC4) on the physiology and regulation in Hepatocellular carcinoma (HCC) and found that epigenetic silencing of ZIC4 by EZH2 mediated
We found that ZIC4 was hypermethylated and downregulated in hepatocellular carcinoma cancer tissues and cells

Summary

Introduction

Liver cancer is the fifth most critical malignant tumor and the second common leading cause of cancer-related death in males, according to statistics, there are about 782,500 people were diagnosed with liver cancer and 745,500 deaths in 2012 all over the world[1]. Hepatocellular carcinoma (HCC) has poor prognosis and is one of the most common type of liver cancer[2]. Many studies have reported that the etiological causes of HCC vary from birth and area, such as intake of alcohol in western countries, hepatitis B virus infection in Africa and East Asia, the infection of hepatitis C virus in Japan and the exposure of aflatoxin B1 in Africa and China[3]. Epigenetic mechanisms such as histone modifications, DNA methylation, non-coding RNAs and chromatin remodeling were proved to regulate gene expression by many cross talk ways[5]. DNA methylation is one of the most widely studied epigenetic mechanisms, which is a covalent modification of DNA, plays an important role in the regulation of genome function, often occurs in hepatocellular carcinoma, bladder cancer, prostate cancer and many other common cancers[6]. It was confirmed that aberrant DNA methylation of promoter CpG islands was involved with the tumor inhibitor

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