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Published online ahead of print on 14 October 2009 as doi:10.1099/vir.0.015149-0
J Gen Virol (2009), DOI 10.1099/vir.0.015149-0
© 2009 Society for General Microbiology
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Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by down-regulating retinoic acid receptor-β2 expression via DNA methylation

Jin Kyu Jung, Sun-Hye Park and Kyung Lib Jang1

Pusan National University

1 E-mail: kljang{at}pusan.ac.kr

Aberrant promoter methylation of retinoic acid receptor-β2 (RAR--β2) is frequently detected in hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC); however, the mechanism and its biological significance are unknown. Here, we report that HBx, the principal oncogene product of HBV, induces promoter hypermethylation of RAR-β2 via up-regulation of DNA methyltransferases 1 and 3a, resulting in down-regulation of its expression in human HCC cells. In addition, HBx abolished the potentials of retinoic acid (RA) to down-regulate levels of G1-checkpoint regulators including p16, p21, and p27, resulting in activation of E2F1 in the presence of RA. As a consequence, HBx-expressing cells compared to the control cells were less susceptible to the RA-induced cell growth inhibition. These effects almost completely disappeared when levels of RAR-β2 in HBx-expressing cells were restored by treatment with a universal DNA methylation inhibitor, 5'Aza-2'dC. Considering that RAR-β2 is a major executor of the anti-tumor potential of RA, its epigenetic down-regulation by HBx should be an important step during HBV-mediated tumorigenesis.

Received 16 July 2009; accepted 13 October 2009.




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