<p>Preferentially expressed antigen in melanoma (PRAME), which is highly expressed in melanoma, is associated with tumor progression and malignancy. Notably, melanoma cells often exhibit inactivation of the tumor suppressor p53 despite carrying the wild-type p53 gene. Here, we investigated the functional interplay between PRAME and p53. Consistent with our analysis of human databases, PRAME overexpression promoted melanoma cell proliferation. Conversely, PRAME downregulation produced the opposite effects, accompanied by an increase in apoptosis. RNA sequencing revealed aberrant regulation of p53 target genes following PRAME depletion, which was further supported by reverse transcription-quantitative polymerase chain reaction and luciferase reporter assays. To explore the underlying mechanism, we isolated the PRAME protein complex and identified DBC1, an SIRT1 suppressor, as a component of the complex. Furthermore, we observed that PRAME promoted p53 deacetylation. The interaction of PRAME with DBC1 releases SIRT1 from DBC1, enabling SIRT1 activation and subsequent p53 deacetylation. The combination of PRAME depletion and SIRT1 inhibition can significantly promote the growth retardation of melanoma cells, as demonstrated by xenograft analysis in nude mice. Collectively, these findings suggest that the acquired elevation of the PRAME level during melanoma pathogenesis may suppress p53 pathways, thereby promoting tumor growth. We propose that PRAME silencing combined with the use of SIRT1 inhibitors is a promising therapeutic strategy for melanoma by restoring p53 activity.</p>