title: All-trans retinoic acid induces p53-depenent apoptosis in human hepatocytes by activating p14 expression via promoter hypomethylation.
abstract: All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, has been extensively studied for the prevention and treatment of cancer; however, the underlying mechanism of its anti-cancer potential is still unclear. Here we found that ATRA induces apoptosis in p53-positive HepG2 cells, but not in p53-negative Hep3B cells. For this effect, ATRA activated p14 expression via promoter hypomethylation, resulting in ubiquitin-dependent degradation of mouse double minute 2 (MDM2) and subsequent stabilization of p53. The potential of ATRA to stabilize p53 was almost completely abolished by knock-down of p14 in HepG2 cells and was not observed in p14-negative A549 cells. Upregulation of p14 also abolished the self-regulatory potential of p53 to repress p14 expression via DNA methylation and transcriptionally activate MDM2 expression. The accumulated p53 then activated several apoptosis-related molecules, including Bax, PUMA, caspase-9, Bid, caspase-8, caspase-3, and PARP. Ectopic expression of DNA methyltransferase 1 almost completely abolished the potential of ATRA to activate the p14-MDM2-p53 pathway and induce p53-dependent apoptosis. Therefore, we conclude that ATRA induces p14 promoter hypomethylation to trigger apoptosis.
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Shin-Hee
authors.initials: SH
authors.lastname: Heo
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Juri
authors.initials: J
authors.lastname: Kwak
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea. Electronic address: kljang@pusan.ac.kr.
authors.forename: Kyung Lib
authors.initials: KL
authors.lastname: Jang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C401561:CDK2AP2 protein, human; D015513:Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014212:Tretinoin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: All-trans retinoic acid; Apoptosis; DNA methylation; p14; p53