Hepatitis B virus X protein upregulates expression of SMYD3 and C-MYC in HepG2 cells

Abstract

The carcinogenic role of Hepatitis B X (HBX) in hepatocellular carcinoma (HCC) remains largely unknown. Histone H3 lysine 4 methyltransferase SMYD3 was found to be over-expressed and have a pro-carcinogenic effect in HCC. The role of HBX in regulating SMYD3 activity and the corresponding C-MYC gene in HCC carcinogenesis was investigated. SMYD3 and C-MYC expression in HBV-negative HepG2 and HBV-positive HepG2.2.15 were detected by real time PCR and Western blot. After transfection of HBX into HepG2, SMYD3 and C-MYC protein expression was detected and the apoptosis and proliferation of hepatoma cells were assayed. After SMYD3 expression in HepG2 with HBX transfection downregulated by siRNA, the corresponding C-MYC expression, cellular apoptosis, and proliferation were assayed by FACS. SMYD3 mRNA and protein and C-MYC protein were significantly higher in HepG2.2.15 than in HepG2. HBX transfection resulted in enhanced SMYD3 and C-MYC expressions, decreased cell apoptosis, and increased cell proliferation in HepG2 cells. Knocking down of SMYD3 in HepG2 with HBX transfection inhibited C-MYC expression and promoted apoptosis. These results suggest that HBX upregulates SMYD3 expression in HepG2, which may promote hepatoma development and progress. C-MYC may act as a down-stream gene in HBX-SMYD3-related hepatocarcinogenesis.

Hepatitis B virus X protein modulates remodelling of minichromosomes related to hepatitis B virus replication in HepG2 cells

“…The possible explanation from some studies is that SET and MYND domain-containing protein 3 (SMYD3) is one of the methyltransferases for H3 lysine 4 (29,30). RNA polymerase II is recruited to the promoter region of SMYD3 gene by HBx, leading to the enhancement of the expression of SMYD3 and cellular activities of HMTs at H3 lysine 4 (30,31). Histone modifications, as well as modifications of the DNA, can influence chromatin structure, induce the remodelling of chromatin and consequently result in gene silencing (27).…”

Hepatitis B Virus X Protein-Induced Aberrant Epigenetic Modifications Contributing to Human Hepatocellular Carcinoma Pathogenesis

“…In particular, the SET and MYND domain-containing 3 (SMYD3) histone H3-K4-specific methyltransferase (HMT) was shown to promote transcriptional activation of genes related to the development of human colorectal carcinoma, breast cancer, and HCC (60,61). HBx upregulation of SMYD3 expression may lead to transactivation of oncogenes, such as C-MYC (62). Overexpression of the C-MYC oncogene has been associated with tumorigenesis in a wide range of human cancers and is known to act by causing inappropriate gene expression that results in autonomous cellular proliferation and inhibition of cellular differentiation (63)(64)(65).…”

Role of DLC1 tumor suppressor gene and MYC oncogene in pathogenesis of human hepatocellular carcinoma: Potential prospects for combined targeted therapeutics

“…Mutagens-carcinogens also target FSs and induce genomic and gene alterations (131). It is possible that damage inflicted at FRA8C may explain the high frequency of MYC overexpression in viral and alcohol-related HCC (128), in addition to the ability of HBV’s X protein to produce such an effect (132). …”