Signal Activation of Hepatitis B Virus–Related Hepatocarcinogenesis by Up-regulation of SUV39h1

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Hepatitis B virus (HBV) X (HBx) protein is associated with hepatocellular carcinogenesis via the induction of malignant transformation and mitochondrial dysfunction. However, the association between HBx and histone methyltransferase in carcinogenesis has not been fully clarified. In the current study, we analyzed the association between HBx and the histone methyltransferase suppressor of variegation 3–9 homolog 1 (SUV39h1) using HBV replication models.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We constructed several HBx and SUV39h1 expression plasmids and analyzed the association between HBx and SUV39h1 with respect to HBV replication and hepatocarcinogenesis.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>SUV39h1 up-regulation was observed in HBV-infected humanized mouse livers and clinical HBV-related hepatocellular carcinoma tissues, indicating that SUV39h1 expression might be regulated by HBV infection. Through in vitro analysis, we determined that the coactivator domain of HBx interacts with the PSET (PostSET) and SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domains of SUV39h1. The expression levels of 4 genes, activating transcription factor 6, α-fetoprotein, growth arrest and DNA damage–inducible 45a, and dual-specificity phosphatase 1, known to induce carcinogenesis via HBx expression, were up-regulated by HBx and further up-regulated in the presence of both HBx and SUV39h1. Furthermore, histone methyltransferase activity, the main function of SUV39h1, was enhanced in the presence of HBx.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We demonstrated that SUV39h1 and HBx enhance each other’s activity, leading to HBx-mediated hepatocarcinogenesis. We propose that regulation of this interaction could help suppress development of hepatocellular carcinoma.</jats:p> </jats:sec>

LncRNA HOTAIR promotes the proliferation and invasion/metastasis of breast cancer cells by targeting the miR-130a-3p/Suv39H1 axis

“…Suv39H1 promotes tumor growth in human carcinoma, and pharmacological suppression of Suv39H1 is an effective approach to inhibit human carcinoma [ 15 , 16 ]. Suv39H1 may regulate the proliferation and metastasis of epithelial ovarian cancer cells [ 17 ].…”

The association between hepatocarcinogenesis and intracellular alterations due to hepatitis B virus infection

“…125 Recently, the contribution of histone methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39h1) to HBV-related HCC has been identified in clinical and experimental studies. 17,123,124 SUV39h1 and HBx enhance each other's activity, leading to HBx-mediated hepatocarcinogenesis. 17 A recent study has revealed that the structural maintenance of chromosomes 5/6 (Smc5/6) complex is associated with extrachromosomal DNA transcription, including HBV replication.…”

Are Humanized Mouse Models Useful for Basic Research of Hepatocarcinogenesis through Chronic Hepatitis B Virus Infection?

“…Other epigenetic modifications, such as histone modifications, are recognized as key intracellular alterations associated with carcinogenesis [129][130][131][132][133][134][135][136]. HBx has been demonstrated to promote HBV-induced HCC pathogenesis by inducing histone modifications [137][138][139][140].…”

“…HBx also recruits the mSin3A/histone deacetylase 1 (HDAC1) or HDAC1/Sp1 complex and contributes to the activation of hepatocarcinogenesis by suppressing tumor suppressor genes [137,138]. Furthermore, histone methyltransferases, such as SET and MYND domain-containing 3 and suppressor of variegation 3-9 homolog 1 (SUV39h1), are also known to be upregulated in HCC tissues [129,130,134,141], and their expression is enhanced by HBx [134,136]. In addition, HBx is involved, directly or indirectly, in the impairment of efficient homologous recombination and is known to induce genomic instability by the inhibition of histone H2B monoubiquitylation and by structural maintenance of chromosome 5/6 (Smc5/6) ubiquitination using a hijacked CRL4 complex [142].…”

“…In addition, HBx is involved, directly or indirectly, in the impairment of efficient homologous recombination and is known to induce genomic instability by the inhibition of histone H2B monoubiquitylation and by structural maintenance of chromosome 5/6 (Smc5/6) ubiquitination using a hijacked CRL4 complex [142]. Although SUV39h1 upregulation is indicated in the HBV-infected humanized mouse model [134], exhaustive analyses, such as chromatin immunoprecipitation sequencing, have not yet been performed using HBV-infected humanized mice. As epigenetic modifications are considered to occur from the early phase of carcinogenesis and to change with disease progression, exhaustive analyses might contribute to the identification of novel therapeutic targets for HCC.…”