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Epigenetic repression of regulator of G‐protein signaling 2 by ubiquitin‐like with PHD and ring‐finger domain 1 promotes bladder cancer progression
Author(s) -
Ying Liang,
Lin Jun,
Qiu Feng,
Cao Ming,
Chen Haige,
Liu Zhihong,
Huang Yiran
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13116
Subject(s) - bladder cancer , dna methylation , cancer research , epigenetics , methylation , biology , gene silencing , cancer , cell growth , cancer cell , microbiology and biotechnology , gene expression , gene , genetics
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.