Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1.
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.
Lee
Jung-Ok
JO
Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, Korea.
Kwun
Hyun Jin
HJ
Jung
Jin Kyu
JK
Choi
Kyung Hee
KH
Min
Do Sik
DS
Jang
Kyung Lib
KL
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
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