Oncogene-dependent function of BRG1 in hepatocarcinogenesis

Pan Wang,Haichuan Wang,Jingxiao Wang,Li Che,Runze Shang,Kairong Cui,Dan Cao,Xin Chen,Keji Zhao,Diego F Calvisi,Kirsten Utpatel,Xinhua Song,Matthias Evert

doi:10.1038/s41419-020-2289-3

Abstract

Hepatocellular carcinoma (HCC) is the major type of primary liver cancer. Genomic studies have revealed that HCC is a heterogeneous disease with multiple subtypes. BRG1, encoded by the SMARCA4 gene, is a key component of SWI/SNF chromatin-remodeling complexes. Based on TCGA studies, somatic mutations of SMARCA4 occur in ~3% of human HCC samples. Additional studies suggest that BRG1 is overexpressed in human HCC specimens and may promote HCC growth and invasion. However, the precise functional roles of BRG1 in HCC remain poorly delineated. Here, we analyzed BRG1 in human HCC samples as well as in mouse models. We found that BRG1 is overexpressed in most of human HCC samples, especially in those associated with poorer prognosis. BRG1 expression levels positively correlate with cell cycle and negatively with metabolic pathways in the Cancer Genome Atlas (TCGA) human HCC data set. In a murine HCC model induced by c-MYC overexpression, ablation of the Brg1 gene completely repressed HCC formation. In striking contrast, however, we discovered that concomitant deletion of Brg1 and overexpression of c-Met or mutant NRas (NRASV12) triggered HCC formation in mice. Altogether, the present data indicate that BRG1 possesses both oncogenic and tumor-suppressing roles depending on the oncogenic stimuli during hepatocarcinogenesis.

Highlights

Primary liver cancer is the sixth most common tumor in the world[1]
We discovered that BRG1 expression levels are upregulated in most human Hepatocellular carcinoma (HCC) samples when compared with non-tumor liver tissues (Fig. 1a), ~ 3% of HCCs have lower BRG1 expression
We found that mRNA expression of BRG1 was significantly higher in HCC when compared with non-tumorous surrounding livers and normal livers (Supplementary Fig. 1A)

Summary

Introduction

Primary liver cancer is the sixth most common tumor in the world[1]. Hepatocellular carcinoma (HCC) is the predominant subtype of liver cancer. Therapeutic approaches for advanced HCC are limited. These HCC patients are eligible to treatment with Sorafenib and Regorafenib multi-kinase inhibitors, but only limited benefits are observed[2]. Immune checkpoint inhibitors have been approved as second line treatment with marked responses, but only in ~20% of patients[3]. It is imperative to elucidate the ATP-dependent chromatin remodeling is involved in controlling chromatin structure that in turn regulates many physiological and pathological processes[4]. Switching/sucrose non-fermentable (SWI/SNF) complexes are members of the family of ATP-dependent chromatinremodeling complexes, which consists of ~15 subunits[5]

Methods

Results

Conclusion