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.
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Loss of PPP2R3B expression correlates with shorter overall survival in melanomas.
“It has been reported that loss of PPP2R3B expression correlates with shorter overall survival in melanomas.”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as van Kempen et al., 2016
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PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer
(2019) · Advances in Cancer Research · doi:10.1016/bs.acr.2019.03.009 · Cited by 93 · see citing works
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- Authors
- van Kempen, L. C. L., Redpath, M., Elchebly, M., Klein, K. O., Papadakis, A. I., Wilmott, J. S., Scolyer, R. A., Edqvist, P.-H., Pontén, F., Schadendorf, D., van Rijk, A. F., Michiels, S., Dumay, A., Helbling-Leclerc, A., Dessen, P., Wouters, J., Stass, M., Greenwood, C. M. T., Ghanem, G. E., van den Oord, J., Feunteun, J., & Spatz, A.
- Affiliations
- Department of Pathology, McGill University, Montreal, Quebec, Canada.
- Lady Davis Institute for Medical Research (CA)
- The University of Sydney (AU)
- Uppsala University (SE)
- Essen University Hospital (DE)
- Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
- Université Paris-Sud (FR)
- Inserm (FR)
- KU Leuven (BE)
- Université Libre de Bruxelles (BE)
- Laboratory of Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.
- Corresponding author
- Spatz, Alan
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2016-12-14
- Volume
- 8
- Issue
- 369
- Pages
- 369ra177-369ra177
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2565787493
- Cited by
- 29
- References
- 35
- Citations by year
- 2025: 7 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 2 · 2016: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Australian National Health
- Medical Research Council
- Cancer Institute New South Wales
- Topics
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- protein phosphatase 2A regulatory subunit, melanoma, tumor suppressor, sex differences, X chromosome inactivation, pseudoautosomal region, CDC6, Cdt1, origin of replication, cell cycle progression, metastasis-free survival, prognosis
- MeSH terms
- Animals, Chromosome Aberrations, DNA Replication, Female, Humans, Male, Melanoma, Neoplasm Metastasis, Neoplasm Transplantation, Nuclear Proteins, Prognosis, Sex Factors, Skin Neoplasms, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Disease Progression, Disease-Free Survival, Gene Dosage, Cell Cycle Proteins, Chromosomes, Human, X, Cell Line, Tumor, Mice, Protein Phosphatase 2, HEK293 Cells
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