title: Deacetylase inhibition in malignant melanomas: impact on cell cycle regulation and survival.
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 G(2)/M phase delay and accumulation of unphosphorylated retinoblastoma protein (pRB) in all cases. TSA significantly induced protein expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in a dose-dependent manner in all cell lines including those not expressing p21(WAF1/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 p27(Kip1), 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 p21(WAF1/CIP1) in melanomas is silenced by deacetylation, and furthermore that inhibition of deacetylation may have potential in anticancer therapy of melanoma patients.
authors.affiliation: Department of Pathology, The Norwegian Radium Hospital, 0310 Oslo, Norway. v.a.florenes@labmed.uio.no
authors.forename: Vivi Ann
authors.initials: VA
authors.lastname: Flørenes
authors.forename: Martina
authors.initials: M
authors.lastname: Skrede
authors.forename: Kjersti
authors.initials: K
authors.lastname: Jørgensen
authors.forename: Jahn M
authors.initials: JM
authors.lastname: Nesland
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006655:Histone Deacetylases