title: Inhibition of bladder cancer invasion by Sp1-mediated BTG2 expression via inhibition of DNA methyltransferase 1.
abstract: Significantly lower endogenous expression of B-cell translocation gene 2 (BTG2) was observed in human muscle-invasive bladder cancers (MIBC) than matched normal tissues and non-muscle invasive bladder cancers (NMIBC). BTG2 expression was inversely correlated with increased expression of the DNA methyltransferases DNMT1 and DNMT3a in MIBC, but not NMIBC, suggesting a potential role for BTG2 expression in muscle invasion of bladder cancer. Over 90% of tumor tissues revealed strong methylation at CpG islands of the BTG2 gene, compared with no methylation in the normal tissues, implying epigenetic regulation of BTG2 expression in bladder carcinogenesis. By using EJ bladder cancer cells and the demethylating agent decitabine, transcription of BTG2 was shown to be up-regulated by inhibiting DNMT1 expression via modification at CpG islands. DNMT1 binding to the BTG2 gene further regulated BTG2 expression by chromatin remodeling, such as H3K9 dimethylation and H3K4 trimethylation, and Sp1 activation. Induced BTG2 expression significantly reduced EJ cell tumorigenesis and invasiveness together with induction of G2 /M arrest. These results demonstrate an important role for the BTG2(/TIS21/PC3) gene in the progression of bladder cancers, and suggest that BTG2(/TIS21/PC3) is a promising epigenetic target for prevention of muscle invasion in human bladder cancers.
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea; Department of Biomedical Sciences, The Graduate School of Ajou University, Suwon, Korea.
authors.forename: Preethi
authors.initials: P
authors.lastname: Devanand
authors.forename: Sun Il
authors.initials: SI
authors.lastname: Kim
authors.forename: Yong Won
authors.initials: YW
authors.lastname: Choi
authors.forename: Seung Soo
authors.initials: SS
authors.lastname: Sheen
authors.forename: Hyunee
authors.initials: H
authors.lastname: Yim
authors.forename: Min Sook
authors.initials: MS
authors.lastname: Ryu
authors.forename: Se Joong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Lim
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D042002:Chromatin Assembly and Disassembly; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007438:Introns; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
chemical_list: C000717967:DNMT3A protein, human; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D016329:Sp1 Transcription Factor; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human; D001374:Azacitidine
keywords: BTG2/TIS21/PC3 gene; DNA methyltransferases; Sp1 transcription factor; muscle-invasive bladder cancer; non-muscle-invasive bladder cancer