Epigenetic repression of regulator of G‐protein signaling 2 by ubiquitin‐like with PHD and ring‐finger domain 1 promotes bladder cancer progression

Ubiquitin‐like with PHD and ring‐finger domain 1 ( UHRF 1) binds to methylated promoters of tumor‐suppressor genes and suppresses gene expression by forming complexes with DNA methyltransferases. Recent studies have shown that repression of regulator of G‐protein signaling ( RGS ) 2 increases cancer cell growth. However, little is known about whether UHRF 1 promotes bladder cancer progression by epigenetic silencing of RGS 2. Here, we show that UHRF 1 expression is increased in bladder cancer cell lines and in most bladder cancer tissues as compared with normal controls. UHRF 1 overexpression increases bladder cancer cell proliferation, whereas inhibition of UHRF 1 suppresses cell proliferation. In bladder cancer cells, UHRF 1 inhibits RGS 2 expression by increasing the methylation of CpG nucleotides of the RGS 2 promoter. DNA methylation analysis showed tumor‐specific TGS 2 promoter methylation in 73% (38/52) of bladder tumors. High UHRF 1 expression of correlated with aberrant TGS 2 promoter methylation in bladder tumors, which results in the loss of TGS 2 expression, as confirmed by demethylation analysis in cell lines. Functionally, re‐expression of RGS 2 partly abrogates UHRF 1‐induced bladder cell proliferation. Furthermore, Kaplan–Meier analysis showed that low TGS 2 expression is significantly correlated with reduced overall survival in patients with bladder cancer. These results demonstrate that epigenetic repression of RGS 2 by UHRF 1 contributes to bladder cancer progression.