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.

Maternal 5mCpG Imprints at the PARD6G-AS1 and GCSAML Differentially Methylated Regions Are Decoupled From Parent-of-Origin Expression Effects in Multiple Human Tissues

“…The PPP2R3B promoter region is unmethylated in healthy and cancerous tissues from males and females (Figure S1 ); thus, it is not subject to gender-related differential methylation or effects of X-chromosome inactivation in women. PPP2R3B is a gonosomal melanoma tumor suppressor gene (van Kempen et al, 2016 ). The amplimer from this region was used as a positive control for the Hpa II restriction enzyme digestion.…”

Engagement with tNOX (ENOX2) to Inhibit SIRT1 and Activate p53-Dependent and -Independent Apoptotic Pathways by Novel 4,11-Diaminoanthra[2,3-b]furan-5,10-diones in Hepatocellular Carcinoma Cells

“…This finding is not surprising, given that the tNOX gene resides on the X chromosome [13] and previous work showed that gender influences the survival of colorectal cancer patients [55,56]. Thus, the gender-related differences in clinical outcomes may reflect a dosage effect on genes expressed from sex chromosomes [57]. Using the online EMBL-EBI database (), we found that tNOX (ENOX2) expression was 2 Log2-fold enhanced in specimens from primary colorectal tumor patients with and without distant metastasis, as assessed in a microarray analysis [58].…”

Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype

“…The authors proposed that the copy-number sensitivity of this locus could explain the gender differences in melanoma incidence and survival. 35 It is possible to speculate that despite its location in the pseudoautosomal region 1 (PAR1) of the X chromosome, sex may alter the effects of PPP2R3B expression in the germline as well. As our patients with duplications were however of both sexes, and the correlation between PPP2R3B expression and survival in the melanoma trancriptomic data was independent of sex, we do not currently have any evidence for such an effect.…”