title: Hepatitis C virus Core protein overcomes all-trans retinoic acid-induced cell growth arrest by inhibiting retinoic acid receptor-β2 expression via DNA methylation.
abstract: Aberrant promoter methylation of tumor suppressor genes including retinoic acid receptor-β2 (RAR-β2) is frequently detected in hepatitis C virus (HCV)-associated hepatocellular carcinoma; however, the mechanism and its significance are relatively unknown. Here, we showed that HCV Core induced promoter hypermethylation of RAR-β2 to inhibit its expression via up-regulation of DNA methyltransferases 1 and 3b. Under the condition, all-trans retinoic acid (ATRA) failed to activate p16 expression and thus could not inactivate the Rb-E2F pathway. Accordingly, Core-expressing cells exhibited resistance to ATRA-induced growth inhibition. Taken together, HCV Core antagonizes ATRA, a natural anti-cancer compound, to stimulate cell growth via epigenetic down-regulation of RAR-β2.
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hyehyeon
authors.initials: H
authors.lastname: Lee
authors.forename: Young-Ju
authors.initials: YJ
authors.lastname: Woo
authors.forename: Soo Shin
authors.initials: SS
authors.lastname: Kim
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Park
authors.forename: Dongho
authors.initials: D
authors.lastname: Choi
authors.forename: Kyung Lib
authors.initials: KL
authors.lastname: Jang
mesh_terms: D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D016174:Hepacivirus; D018936:Hepatitis C Antigens / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms; D008780:Methyltransferases / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014758:Viral Core Proteins / Q000378:metabolism*
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018936:Hepatitis C Antigens; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C082925:retinoic acid receptor beta; D014212:Tretinoin; D008780:Methyltransferases