Deficiency of histone H3K36 methyltransferase SETD2 inhibits proliferation and migration of hepatocellular carcinoma through ERK pathway

Abstract

Abstract Background Hepatocellular carcinoma (HCC) is one of the leading cause of cancer-related death worldwide. SETD2, as the only known methyltransferase for catalyzing trimethylation of histone H3 lysine 36 (H3K36), has been reported to be associated with several cancers. However, the function of SETD2 in HCC is ambiguous. This work aims to research the function and mechanism of SETD2 in HCC based on bioinformation analysis and cell experiments. Methods SETD2 expression and its relationship with prognosis in LIHC patients were evaluated based on the Cancer Genome Atlas (TCGA) database, the effect of SETD2 silencing and overexpression on HCC cell lines was explored according to CCK-8 assay, colony formation assay and wound healing assay. RNA-seq analysis, western blot and chromatin immunoprecipitation (ChIP) assay were used to explore the potential mechanism of SETD2 in HCC. Results The results indicated that SETD2 expression was upregulated and high SETD2 expression was related to poor prognosis in HCC. SETD2 silencing inhibited the proliferation and migration, and SETD2 overexpression promoted the proliferation and migration in HCC cells. RNA-seq data revealed that differentially expressed genes were dramatically enriched in fibroblast growth factor receptor signaling pathway. FGFBP1, as a FGF-binding protein, ranked in the top 10 among the DEGs. The expression of FGFBP1 in SETD2 silencing BEL-7402 cells was significantly decreased. As the downstream effector of FGFR, ERK phosphorylation level had positive correlation with SETD2. Besides, H3K36me3 directly bound to the promoter of FGFBP1 confirmed by ChIP-qPCR. Conclusions Our findings highlight the promotion role of SETD2/H3K36me3 in HCC proliferation and migration via FGFR-ERK signal pathway. Our studies will advance our understanding of epigenetic dysregulation at HCC progression and provide a rationale for SETD2 as potential diagnostic biomarker and therapeutic target in HCC.