Historic deacetylase (HDAC) inhibitors have shown promise in clinical cancer therapy and to consistently induce p21(WAF1/C1P1) expression in a p53-independent manner and via increased acetylation of the chromatin at the Sp1 sites in the p21(WAF1/CIP1) promoter region. However, the exact mechanism by which HDAC inhibitors induce p21(WAF1/CIP1) remains unclear. In this study, we observed that Trichostatin A (TSA), a HDAC inhibitor, induced strikingly p21(WAF1/CIp1) expression in human cervical cancer (HeLa) cells, and this induction correlated with downregulation of c-myc expression. Coincident with this observation, knock down of c-myc with a c-myc specific small interfering RNA dramatically induced expression of p21(WAF1/CIP1) in these cancer cells. These data suggest that c-myc may play a critical role in repression of p21(WAF1/CIP1) 1 expression in HeLa cells. More importantly, using chromatin immunoprecipitation assay, we observed for the first time that c-myc bound to the endogenous p21(WAF1/CIP1) promoter in untreated HeLa cells, but not in TSA-treated cells. Taken together, TSA induced c-myc downregulation and release from the endogenous p21(WAF1/CIP1) promoter contributes, at least partially, to transcriptional activation of the p21(WAF1/CIP1) in HeLa cells. (C) 2004 Elsevier Inc. All rights reserved.