Deficiency of the histone H3K36 methyltransferase SETD2 inhibits the proliferation and migration of hepatocellular carcinoma cells

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. SETD2, the only known methyltransferase catalyzes the trimethylation of histone H3 lysine 36 (H3K36), has been reported to be associated with several cancers. However, the function of SETD2 in HCC is unclear. This work aimed to investigate the function and mechanism of SETD2 in HCC through bioinformatics analysis and cell experiments. Methods: SETD2 expression and its relationship with prognosis were evaluated in The Cancer Genome Atlas (TCGA)-LIHC cohort, and the effects of SETD2 silencing and overexpression on HCC cell lines were assesed via CCK-8, colony formation and wound healing assays. RNA-seq analysis, western blotting and chromatin immunoprecipitation (ChIP) assays were used to assess the potential mechanism of action of SETD2 in HCC. Results: The results indicated that SETD2 expression is upregulated and that high SETD2 expression is related to a poor prognosis in HCC patients. SETD2 silencing inhibited proliferation and migration, and SETD2 overexpression promoted proliferation and migration in HCC cells. RNA-seq data revealed that the differentially expressed genes were enriched in the fibroblast growth factor receptor signaling pathway. FGFBP1, which was an FGF-binding protein and could enhance FGFR signaling pathway by releasing FGF from the extracellular matrix, was among the top 10 DEGs. Furthermore, the expression of FGFBP1 was decreased in SETD2-silenced BEL-7402 cells. The expression level of phosphorylated ERK, a downstream effector of FGFR, was positively correlated with the expression level of SETD2. In addition, ChIP-qPCR confirmed that the H3K36me3 modification occured on the gene body of FGFBP1. Conclusions: Our findings highlight the role of SETD2/H3K36me3 in promoting HCC proliferation and migration via the FGFR pathway. Our study advances our understanding of epigenetic dysregulation during HCC progression and provides a rationale for the application of SETD2 as a potential diagnostic biomarker and therapeutic target in HCC.