Acetylation of PML Plays a Key Role in Histone Deacetylase Inhibitor-Mediated Apoptosis through Enhanced PML Sumoylation.

The promyelocytic leukemia (PML) protein is a potent tumor suppressor and proapoptotic factor, and is functionally regulated by posttranslational modification such as phosphorylation, sumoylation, and ubiquitination. Histone deacetylase (HDAC) inhibitors are a promising class of targeted anticancer agents and induce apoptosis to cancer cells. In addition to their effects on histones, HDAC inhibitors increase the acetylation level of several non-histone proteins such as transcription factors, which are important for their effects to cancer cells. However, the mechanism of HDAC inhibitor-induced apoptocis is largely unknown. We report here a novel posttranscriptional modification, acetylation, of PML. By the screening using antibody array, we identified PML as a new acetylation target of Trichostatin A (TSA), a HDAC inhibitor. PML acetylation was enhanced by coexpression of p300 or treatment with TSA. We also showed that increased PML acetylation was associated with increased sumoylation of PML in vitro and in vivo. PML involvement in TSA-induced apoptosis was demonstrated by PML knocking down in Hela cells or PML overexpression in PML−/− MEF cells. Furthermore, PML with acetylation-defective mutation showed disability to mediate the apoptosis, suggesting the importance of PML acetylation for it. Our work provides new insights into the PML regulation by posttranslational modification, and new information about the therapeutic mechanism of HDAC inhibitors.