PPP2R3B Is a Sex-Linked Melanoma Tumor Suppressor Gene

In patients with melanoma, males tend to have a poorer prognosis than females, but the biological mechanisms underlying this sex difference have not been elucidated. Van Kempen and colleagues hypothesized that differences in gene dosage from the sex chromosomes might contribute to the sex differences in melanoma. Analysis of primary melanomas revealed that loss of the inactive X chromosome (Xi) is associated with a poorer distant metastasis-free survival. Moreover, men with Y chromosome loss also had a poorer prognosis, prompting the investigation of the pseudoautosomal region (PAR), which is present on both the X and Y chromosomes and commonly escapes inactivation on Xi. Decreased expression of one PAR gene, protein phosphatase 2 regulatory subunit B, beta (PPP2R3B), encoding PR70, was associated with shorter survival in patients with melanoma. Despite its location within the PAR, PPP2R3B expression was lower in males than in females, and in females, loss of Xi also resulted in reduced expression. In melanoma cell lines, high PPP2R3B expression was associated with reduced cell growth, and overexpression of PR70 prevented 3-D colony formation. Further, overexpression of PR70 reduced melanoma xenograft growth in vivo, suggesting a role as a tumor suppressor. However, in contrast to classic tumor suppressor genes, PPP2R3B is not frequently mutated in melanoma. Mechanistically, PR70 overexpression disrupted the interaction between CDC6 and CDT1, which is crucial in initiating the firing of DNA replication origins. Thus, PR70 overexpression delayed the progression from G1 to S phase by limiting replication origin firing. Altogether, these findings identify PPP2R3B as a sex-linked tumor suppressor gene and suggest that its differential expression may explain the poorer prognosis in male patients with melanoma.

van Kempen LC, Redpath M, Elchebly M, Klein KO, Papadakis AI, Wilmott JS, et al. The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene. Sci Transl Med 2016;8:369ra177.

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