All-trans retinoic acid induces p53-depenent apoptosis in human hepatocytes by activating p14 expression via promoter hypomethylation

作者：Heo Shin Hee; Kwak Juri; Jang Kyung Lib^*

来源：Cancer Letters, 2015, 362(1): 139-148.

DOI：10.1016/j.canlet.2015.03.036

• All-trans retinoic acid
• Apoptosis
• DNA methylation
• p53
• p14

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 anticancer 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 I 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.

• 出版日期2015-6-28