The roles of mutated SWI/SNF complexes in the initiation and development of hepatocellular carcinoma and its regulatory effect on the immune system: A review

Abstract

Hepatocellular carcinoma (HCC) is a primary liver malignancy with a high global prevalence and a dismal prognosis. Studies are urgently needed to examine the molecular pathogenesis and biological characteristics of HCC. Chromatin remodelling, an integral component of the DNA damage response, protects against DNA damage-induced genome instability and tumorigenesis by triggering the signalling events that activate the interconnected DNA repair pathways. The SWI/SNF complexes are one of the most extensively investigated adenosine triphosphate-dependent chromatin remodelling complexes, and mutations in genes encoding SWI/SNF subunits are frequently observed in various human cancers, including HCC. The mutated SWI/SNF complex subunits exert dual functions by accelerating or inhibiting HCC initiation and progression. Furthermore, the abnormal SWI/SNF complexes influence the transcription of interferon-stimulated genes, as well as the differentiation, activation and recruitment of several immune cell types. In addition, they exhibit synergistic effects with immune checkpoint inhibitors in the treatment of diverse tumour types. Therefore, understanding the mutations and deficiencies of the SMI/SNF complexes, together with the associated functional mechanisms, may provide a novel strategy to treat HCC through targeting the related genes or modulating the tumour microenvironment.

Keywords: SWI/SNF complex; chromatin remodelling; hepatocellular carcinoma; immunotherapy; tumour suppressor gene.

FIGURE 1

High‐frequency gene mutation of BAF in different tumours. The sources are shown in brackets. BAF, BRG1‐associated factor

FIGURE 2

High‐frequency gene mutation of PBAF in different tumours. The sources are shown in brackets. PBAF, polybromo BAF

FIGURE 3

Hypothetical models for the function of residual BRM‐SWI/SNF complexes in BRG1‐mutant cancers. A, Paralog insufficiency model. In the cancer cell of origin, BRG1 and BRM perform redundant functions in supporting cell viability, while BRG1 performs a non‐redundant tumour suppressor function. Loss of BRG1 would lead to tumorigenic effects while simultaneously rendering BRM the sole ATPase subunit responsible for supporting tumour cell viability. B, Paralog antagonism model. In the cancer cell of origin, BRG1 performs a specific function in tumour protection, while BRM promotes oncogenesis, resulting in a balanced state of SWI/SNF functions. Loss of BRG1 would result in unopposed BRM‐driven proliferation and tumorigenesis. C, Aberrant complex model. Loss of BRG1 would release specific subunits of its dedicated protein complex, which would form aberrant associations with BRM that deregulate cancer‐relevant transcriptional programmes

FIGURE 4

The effect of SWI/SNF complex on the proliferation and differentiation of several immune cells. See the main text for detailed description of the relationship shown. CCR2, chemokine receptor 2; CXCL3, CXC chemokine receptor 3; Treg, regulatory T cells; TH, T helper; CCL4, C‐C motif chemokine 4‐like; IL‐8, interleukin‐8

FIGURE 5

Loss of PBAF could improve the expression of ISGs. Loss of PBAF is proposed to alter chromatin structure so that IFN‐g response elements in ISG promoters are more accessible to transcription factors, increasing their expression. When PBAF is intact, it might cooperate with EZH2 to modify chromatin and reduce the accessibility to IFN‐g response elements. PBAF, polybromo BAF; ISGs, interferon‐stimulated genes