van Kempen LC, Redpath M, Elchebly M, Klein KO, Papadakis AI, Wilmott JS, Scolyer RA, Edqvist PH, Pontén F, Schadendorf D, van Rijk AF, Michiels S, Dumay A, Helbling-Leclerc A, Dessen P, Wouters J, Stass M, Greenwood CM, Ghanem GE, van den Oord J, Feunteun J, Spatz A
Sci Transl Med 8 (369) 369ra177 [2016-12-14; online 2016-12-16]
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 hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate 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 from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the cell division cycle 6 (CDC6)-chromatin licensing and DNA replication factor 1 (CDT1) interaction, which delays the firing of origins of DNA replication. Hence, PR70 functionally behaves as an X-linked tumor suppressor gene.