Histone deacetylase inhibitors activate p21(WAF1) expression via ATM.

Histone deacetylase (HDAC) inhibitors are known to induce expression of genes such as p21(WAF1), thereby, leading to cell cycle arrest. In this work, we show that p21(WAF1) induction by HDAC inhibitors (depsipeptide and trichostatin A) is defective in Ataxia telangiectasia (AT) cells but normal in matched wild-type (WT) cells (human diploid fibroblasts). To verify the role of ATM in this effect, we show that ectopic expression of the WT ATM gene in an AT cell line fully restores p21(WAF1) induction by the HDAC inhibitors. Furthermore, because caffeine and wortmannin attenuate p21(WAF1) induction in WT cells, it is probable that the phosphatidylinositol 3'-kinase activity is essential for this process. Besides the p21(WAF1) promoter, activation of topoisomerase IIIalpha and SV40 promoters by the HDAC inhibitors are also decreased in the AT cell lines relative to WT cells; thus, these findings pertain to other promoters. Finally, despite the obvious induction deficiency of gene expression, the overall levels of H3 and H4 histone acetylation appear to be the same between AT and normal cells in response to HDAC inhibitor treatments. Taken together, the data indicate that ATM is involved in histone acetylation-mediated gene regulation.