ORIGINAL ARTICLESDeacetylase inhibition in malignant melanomas: impact on cell cycle regulation and survivalFlørenes, Vivi Ann; Skrede, Martina; Jørgensen, Kjersti; Nesland, Jahn M.Author Information Department of Pathology, The Norwegian Radium Hospital, 0310 Oslo, Norway Sponsorship: This work was supported by the Norwegian Cancer Society. Correspondence and requests for reprints to Dr Vivi Ann Flørenes, Department of Pathology, The Norwegian Radium Hospital, 0310 Oslo, Norway Tel: +47 22 93 41 94; fax: +47 22 73 01 64; e-mail: [email protected] Received 13 October 2003 Accepted 13 February 2004 Melanoma Research: June 2004 - Volume 14 - Issue 3 - p 173-181 doi: 10.1097/01.cmr.0000129576.49313.26 Buy Metrics Abstract In the present study the deacetylase inhibitor trichostatin A (TSA) was used to elucidate the effect of protein acetylation on cell cycle progression and survival in seven human malignant melanoma cell lines. It was shown that TSA treatment led to a transient G2/M phase delay and accumulation of unphosphorylated retinoblastoma protein (pRB) in all cases. TSA significantly induced protein expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in a dose-dependent manner in all cell lines including those not expressing p21WAF1/CIP1 constitutively, whereas the levels of both wild-type and mutated p53 protein were reduced. The effect on p53 was not a direct result of inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) activation by TSA, as treatment of the cells with the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) inhibitor PD98059 did not result in decreased p53 protein level. Furthermore, TSA treatment led to reduction in cyclin D1 whereas cyclin D3 accumulated, the latter due to increased protein stability. Similarly, cyclin A protein was reduced whereas cyclin E level was elevated. The effect on p27Kip1, CDK4 and CDK2 was only marginal. In all the examined cell lines, TSA treatment resulted in a profound induction of apoptosis and cleavage of poly-(ADP-ribose)-polymerase (PARP) indicative of caspase activity. Similarly, TSA-mediated apoptosis was reversed by the caspase-inhibitor z-vad-fmk. Altogether, these results suggest that p21WAF1/CIP1 in melanomas is silenced by deacetylation, and furthermore that inhibition of deacetylation may have potential in anticancer therapy of melanoma patients. © 2004 Lippincott Williams & Wilkins, Inc.