Research ArticleCancer

The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene

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Science Translational Medicine  14 Dec 2016:
Vol. 8, Issue 369, pp. 369ra177
DOI: 10.1126/scitranslmed.aai9188

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XX multitasks; XY not so much

A new X-linked tumor suppressor gene that escapes X inactivation drives higher expression of its encoded protein PR70—the regulatory subunit of protein phosphatase 2A—in females and might explain the worse prognoses observed in men with melanoma, relative to women. The authors showed that in melanoma, the most serious type of skin cancer, loss of an inactivated X chromosome from females was strongly associated with poor distant metastasis–free survival, an observation that suggests a dosage benefit with two functional X chromosomes. The authors then correlated survival with PR70 expression in 49 patient samples and separately validated this finding in another 234 samples. On the other hand, loss of an active copy of PR70 from an inactivated X chromosome appeared to act as a driver of melanoma, as expected for a tumor suppressor. The authors then showed that increased PR70 expression slowed the growth of melanoma cell lines in vitro and tumorigenicity in vivo. Mechanistic studies revealed that the PR70 protein slowed cell growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the CDC6-CDT1 interaction, which delays the firing of origins of DNA replication.

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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