title: Epigenetic repression of regulator of G-protein signaling 2 by ubiquitin-like with PHD and ring-finger domain 1 promotes bladder cancer progression.
abstract: Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) 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 UHRF1 promotes bladder cancer progression by epigenetic silencing of RGS2. Here, we show that UHRF1 expression is increased in bladder cancer cell lines and in most bladder cancer tissues as compared with normal controls. UHRF1 overexpression increases bladder cancer cell proliferation, whereas inhibition of UHRF1 suppresses cell proliferation. In bladder cancer cells, UHRF1 inhibits RGS2 expression by increasing the methylation of CpG nucleotides of the RGS2 promoter. DNA methylation analysis showed tumor-specific TGS2 promoter methylation in 73% (38/52) of bladder tumors. High UHRF1 expression of correlated with aberrant TGS2 promoter methylation in bladder tumors, which results in the loss of TGS2 expression, as confirmed by demethylation analysis in cell lines. Functionally, re-expression of RGS2 partly abrogates UHRF1-induced bladder cell proliferation. Furthermore, Kaplan-Meier analysis showed that low TGS2 expression is significantly correlated with reduced overall survival in patients with bladder cancer. These results demonstrate that epigenetic repression of RGS2 by UHRF1 contributes to bladder cancer progression.
authors.affiliation: Department of Urology, Renji Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ying
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.forename: Ming
authors.initials: M
authors.lastname: Cao
authors.forename: Haige
authors.initials: H
authors.lastname: Chen
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
authors.forename: Yiran
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000368:Aged; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D020710:RGS Proteins; C087182:RGS2 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: bladder cancer; cell proliferation; methylation; regulator of G-protein signaling 2; ubiquitin-like with PHD and ring-finger domain 1