All-trans retinoic acid induces cellular senescence by up-regulating levels of p16 and p21 via promoter hypomethylation

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.

► ATRA induced promoter hypomethylation of p16 and p21 via down-regulation of DNA methyltransferases 1, 3a, and 3b. ► Transcriptional activators Ets1/2 and p53 were more efficiently recruited to the p16 and p21 promoters, respectively. ► Upregulation of p16 and p21 by ATRA resulted in induction of cellular senescence in HepG2 cells. ► RAR-β2 mediated the potential of ATRA to induce cellular senescence.