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Histone deacetylases inhibitors (HDIs) induce growth arrest and apoptosis in a variety of human cancer cells. Sodium butyrate (NaB), a histone deacetylase inhibitor, has been shown to cause a G1 cell cycle arrest by inducing p21WAF1/CIP1 in ap53-independent manner. In this report, we present evidence for activation ofp53pathway by NaB and its role in the NaB-mediated growth suppression. Addition of NaB increased the levels of p53 involving a p14ARF-dependent post-transcriptional mechanism. NaB induced p53 is functional as it activatedp53-specific reporter, induced the level of p21WAF1/CIP1, inhibited cellular DNA synthesis and induced apoptosis. By using HPV 16 E6 stable transfectants as well asp53null cancer cells, we show that NaB suppresses the growth of WTp53containing cells more efficiently. NaB inhibited DNA synthesis to similar extent both in the presence and absence of p53. However, NaB treatment lead to a major G2/M arrest of cells in the presence of p53, while cells without wild-type p53 accumulated mainly in G1 phase of the cell cycle. Furthermore, apoptosis induction by NaB is greatly reduced in the absence of p53. These results suggest thatp53pathway mediates in part growth suppression by NaB and thep53status may be an important determinant of chemosensitivity in HDI based cancer chemotherapy. © 2005 Wiley-Liss, Inc.