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Tumor antigen PRAME promotes melanoma growth by inactivating p53 through the SIRT1-DBC1 axis

Oncogene volume 44, pages 4087–4099 (2025)Cite this article

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Abstract

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.

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Fig. 1: PRAME is highly expressed in melanoma and promotes cell proliferation.
Fig. 2: PRAME knockdown leads to aberrant expression of p53 target genes.
Fig. 3: PRAME suppresses the expression of p53 target genes.
Fig. 4: DBC1 is identified as a component of the PRAME complex.
Fig. 5: PRAME suppresses p53 acetylation, which is hindered by SIRT1 inhibition.
Fig. 6: PRAME disrupts the DBC1-SIRT1 interaction and facilitates p53 deacetylation in vitro.
Fig. 7: PRAME depletion and SIRT1 inhibition significantly enhance tumor regression.
Fig. 8: Hypothetical model for PRAME-mediated p53 inactivation in melanoma development.

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Data availability

The RNA-seq data from PRAME-depleted A375SM melanoma cells have been deposited in NCBI’s Gene Expression Omnibus (GEO) under accession number GSE306132.

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Acknowledgements

We thank Dr. Bert Vogelstein (Howard Hughes Medical Institute, Johns Hopkins Oncology Center) for providing p21WAF1 and MDM2 promoter-luciferase reporter constructs.

Funding

This study was supported in part by the Basic Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (2022R1F1A1068623 to E.J.K.), by the National Research Foundation of Korea grant funded by the Korea government (MSIT) (RS-2025-00562288 to S.J.U.), and by Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education (RS-2023-NF001356 to S.J.U.).

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Author notes

  1. These authors contributed equally: Yong-Kyu Lee, Hyeon Ho Heo.

Authors and Affiliations

  1. Department of Integrative Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul, 05006, South Korea

    Yong-Kyu Lee, Hyeon Ho Heo, Ui-Hyun Park, HyeSook Youn & Soo-Jong Um

  2. Department of Molecular Biology, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan, 31116, South Korea

    Eun-Joo Kim

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Contributions

Conceptualization, Y.K.L., H.H.H., H.Y., E.J.K., and S.J.U.; methodology, Y.K.L., H.H.H., U.H.P., and H.Y.; investigation, data curation, and visualization, Y.K.L., H.H.H.; writing, Y.K.L., H.H.H., E.J.K., and S.J.U.; supervision and funding acquisition, E.J.K. and S.J.U. All authors have read and agreed to submit this version of the manuscript.

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Correspondence to Eun-Joo Kim or Soo-Jong Um.

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All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Sejong University (Approval No. SJ-20240111-02E1) and conducted in accordance with institutional guidelines.

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Lee, YK., Heo, H.H., Park, UH. et al. Tumor antigen PRAME promotes melanoma growth by inactivating p53 through the SIRT1-DBC1 axis. Oncogene 44, 4087–4099 (2025). https://doi.org/10.1038/s41388-025-03565-z

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