title: Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1.
abstract: E-cadherin is a key cell adhesion molecule implicated as a tumor suppressor, which is frequently altered in hepatocellular carcinoma, especially in hepatitis B virus (HBV)-related tumors. Here, we report that HBV X protein (HBx) represses E-cadherin expression at the transcription level. Based on the differential effects of HBx natural variants, we determined that Lys-130 in the transactivation domain of HBx is critical for the E-cadherin repression. The repression effect of HBx was abolished after treatment with DNA methyltransferase inhibitor, 5'-Aza-2'dC. In addition, methylation-specific PCR analysis revealed that the CpG island 1 of E-cadherin promoter is hypermethylated by HBx. Furthermore, HBx induces DNA methyltransferase 1 expression by stimulating its transcription. Therefore, we conclude that HBx represses E-cadherin expression by inducing methylation-mediated promoter inactivation. The reduced E-cadherin expression results in dramatic morphological changes of the HBx-expressing cells. In addition, HBx-expressing cells aggregate poorly in suspension culture, reflecting their altered intercellular interactions. The biological significance was further demonstrated by the increased collagen invasion ability of HBx-expressing cells. Therefore, the present study suggests that HBx plays a role during hepatocellular carcinogenesis by favoring cell detachment from the surrounding cells and migration outside of the primary tumor site.
authors: Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, Korea.
authors: Jung-Ok
authors: JO
authors: Lee
authors: Hyun Jin
authors: HJ
authors: Kwun
authors: Jin Kyu
authors: JK
authors: Jung
authors: Kyung Hee
authors: KH
authors: Choi
authors: Do Sik
authors: DS
authors: Min
authors: Kyung Lib
authors: KL
authors: Jang
mesh_terms: D001483:Base Sequence; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019175:DNA Methylation; D017931:DNA Primers; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D015820:Cadherins; C411744:DMAP1 protein, human; D017931:DNA Primers; D012097:Repressor Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein