Inhibition of bladder cancer invasion by Sp1‐mediated BTG 2 expression via inhibition of DNA methyltransferase 1
2014; Wiley; Volume: 281; Issue: 24 Linguagem: Inglês
10.1111/febs.13099
ISSN1742-4658
AutoresPreethi Devanand, Sun Il Kim, Yong Won Choi, Seung Soo Sheen, Hyunee Yim, Min Sook Ryu, Se Joong Kim, Wun‐Jae Kim, In Kyoung Lim,
Tópico(s)RNA modifications and cancer
ResumoSignificantly lower endogenous expression of B‐cell translocation gene 2 ( BTG 2) was observed in human muscle‐invasive bladder cancers ( MIBC ) than matched normal tissues and non‐muscle invasive bladder cancers ( NMIBC ). BTG 2 expression was inversely correlated with increased expression of the DNA methyltransferases DNMT 1 and DNMT 3a in MIBC , but not NMIBC , suggesting a potential role for BTG 2 expression in muscle invasion of bladder cancer. Over 90% of tumor tissues revealed strong methylation at CpG islands of the BTG 2 gene, compared with no methylation in the normal tissues, implying epigenetic regulation of BTG 2 expression in bladder carcinogenesis. By using EJ bladder cancer cells and the demethylating agent decitabine, transcription of BTG 2 was shown to be up‐regulated by inhibiting DNMT 1 expression via modification at CpG islands. DNMT 1 binding to the BTG 2 gene further regulated BTG 2 expression by chromatin remodeling, such as H3K9 dimethylation and H3K4 trimethylation, and Sp1 activation. Induced BTG 2 expression significantly reduced EJ cell tumorigenesis and invasiveness together with induction of G 2 /M arrest. These results demonstrate an important role for the BTG 2 /TIS21/PC3 gene in the progression of bladder cancers, and suggest that BTG 2 /TIS21/PC3 is a promising epigenetic target for prevention of muscle invasion in human bladder cancers.
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