The Protein Phosphatase 2a Regulatory Subunit Pr70 Is A Gonosomal Melanoma Tumor Suppressor Gene

Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesize that gene expression from gonosomes may play an important role. The current study demonstrates that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit of two X-chromosomes. The gonosomal PPP2R3B gene is located on the pseudo-autosomal region (PAR) of the X-chromosome in females and on the Y-chromosome in males. We observed that despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression is lower in males than in females, and is independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate recognizing subunit of PP2A, that decreases melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing CDC6/CDT1 interaction that delays the firing of origins of DNA replication. As such, PR70 behaves functionally as an X-linked tumor suppressor gene. Citation Format: Leon C.L. Van Kempen, Margaret Redpath, Mounib Elchebly, Kathleen Oros Klein, Andreas Papadakis, James Willmott, Richard Scolyer, Per-Henrik Edqvist, Fredrik Ponten, Dirk Schadendorf, Anke van Rjk, Stefan Michiels, Anne Dumay, Anne Helbling-Leclerc, Philippe Dessen, Jasper Wouters, Marguerite Stass, Celia Greenwood, G. Elias Ghanem, Joost van den Oord, Jean Feunteun, Alan Spatz. The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5528. doi:10.1158/1538-7445.AM2017-5528