title: All-trans retinoic acid induces cellular senescence by up-regulating levels of p16 and p21 via promoter hypomethylation.
abstract: All-trans retinoic acid (ATRA) induces cellular senescence via up-regulation of p16 and p21; however, the action mechanism of ATRA is unknown. Here, we show that ATRA induces promoter hypomethylation of p16 and p21 via down-regulation of DNA methyltransferases 1, 3a, and 3b to facilitate binding of Ets1/2 to the p16 promoter and p53 to the p21 promoter, resulting in up-regulation of their expression and subsequent induction of cellular senescence in HepG2 cells. These effects were mediated by retinoic acid receptor β₂ whose promoter was also hypomethylated in the presence of ATRA. Therefore, ATRA can be considered as an epi-drug in cancer therapy.
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Joo Song
authors.initials: JS
authors.lastname: Lim
authors.forename: Sun-Hye
authors.initials: SH
authors.lastname: Park
authors.forename: Kyung Lib
authors.initials: KL
authors.lastname: Jang
mesh_terms: D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C494041:ETS1 protein, human; C494069:ETS2 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2; C533416:RARB2 protein, human; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D004248:DNA (Cytosine-5-)-Methyltransferases