Tumor antigen PRAME is a potential therapeutic target of p53 activation in melanoma cells
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Upregulation of PRAME (preferentially expressed antigen of melanoma)has been implicated in the progression of a variety ofcancers, including melanoma. The tumor suppressor p53 is atranscriptional regulator that mediates cell cycle arrest and apoptosisin response to stress signals. Here, we report that PRAMEis a novel repressive target of p53. This was supported by analysisof melanoma cell lines carrying wild-type p53 and humanmelanoma databases. mRNA expression of PRAME was downregulatedby p53 overexpression and activation using DNA-damagingagents, but upregulated by p53 depletion. We identifieda p53-responsive element (p53RE) in the promoter regionof PRAME. Luciferase and ChIP assays showed that p53 repressesthe transcriptional activity of the PRAME promoter andis recruited to the p53RE together with HDAC1 upon etoposidetreatment. The functional significance of p53 activationmediatedPRAME downregulation was demonstrated by measuringcolony formation and p27 expression in melanoma cells. These data suggest that p53 activation, which leads to PRAMEdownregulation, could be a therapeutic strategy in melanomacells.
Abstract
Upregulation of PRAME (preferentially expressed antigen of melanoma)has been implicated in the progression of a variety ofcancers, including melanoma. The tumor suppressor p53 is atranscriptional regulator that mediates cell cycle arrest and apoptosisin response to stress signals. Here, we report that PRAMEis a novel repressive target of p53. This was supported by analysisof melanoma cell lines carrying wild-type p53 and humanmelanoma databases. mRNA expression of PRAME was downregulatedby p53 overexpression and activation using DNA-damagingagents, but upregulated by p53 depletion. We identifieda p53-responsive element (p53RE) in the promoter regionof PRAME. Luciferase and ChIP assays showed that p53 repressesthe transcriptional activity of the PRAME promoter andis recruited to the p53RE together with HDAC1 upon etoposidetreatment. The functional significance of p53 activationmediatedPRAME downregulation was demonstrated by measuringcolony formation and p27 expression in melanoma cells. These data suggest that p53 activation, which leads to PRAMEdownregulation, could be a therapeutic strategy in melanomacells.
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