title: The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene.
abstract: 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.
authors.affiliation: Department of Pathology, McGill University, Montreal, Quebec, Canada.|Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors.forename: Léon C L
authors.initials: LC
authors.lastname: van Kempen
authors.affiliation: Department of Pathology, McGill University, Montreal, Quebec, Canada.|Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors.forename: Margaret
authors.initials: M
authors.lastname: Redpath
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors.forename: Mounib
authors.initials: M
authors.lastname: Elchebly
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors.forename: Kathleen Oros
authors.initials: KO
authors.lastname: Klein
authors.affiliation: Department of Pathology, McGill University, Montreal, Quebec, Canada.|Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors.forename: Andreas I
authors.initials: AI
authors.lastname: Papadakis
authors.affiliation: Melanoma Institute Australia, Royal Prince Alfred Hospital, and University of Sydney, Sydney, New South Wales, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Melanoma Institute Australia, Royal Prince Alfred Hospital, and University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Edqvist
authors.affiliation: Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Department of Dermatology, University Hospital Essen, Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors.forename: Anke F
authors.initials: AF
authors.lastname: van Rijk
authors.affiliation: Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif, France.|Centre for Research in Epidemiology and Population Health (CESP), INSERM, UMR 1018, Université Paris-Sud, Kremlin-Bicetre, France.
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.affiliation: Centre de Recherche sur l'Inflammation, INSERM, UMR S 1149, Labex Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Dumay
authors.affiliation: CNRS, UMR 8200, Université Paris-Sud, Villejuif, France.|CNRS UMR 8200, Universite Paris-Sud, Gustave Roussy, Villejuif, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Helbling-Leclerc
authors.affiliation: Hématopoïèse normale et pathologique, INSERM UMR 1170, Université Paris-Sud, Gustave Roussy, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.affiliation: Laboratory of Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.|Laboratory of Computational Biology, VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium.|Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Jasper
authors.initials: J
authors.lastname: Wouters
authors.affiliation: Department of Surgical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Stass
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.|Department of Oncology, McGill University, Montreal, Quebec, Canada.|Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada.
authors.forename: Celia M T
authors.initials: CM
authors.lastname: Greenwood
authors.affiliation: Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Ghanem E
authors.initials: GE
authors.lastname: Ghanem
authors.affiliation: Laboratory of Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: van den Oord
authors.affiliation: CNRS UMR 8200, Universite Paris-Sud, Gustave Roussy, Villejuif, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Feunteun
authors.affiliation: Department of Pathology, McGill University, Montreal, Quebec, Canada. alan.spatz@mcgill.ca.|Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.|Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Spatz
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D041321:Chromosomes, Human, X; D004261:DNA Replication; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D012878:Skin Neoplasms / Q000378:metabolism*
chemical_list: C103706:CDC6 protein, human; C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C403618:PPP2R3B protein, human; D054648:Protein Phosphatase 2