Inhibition of bladder cancer invasion by Sp1‐mediated <scp>BTG</scp>2 expression via inhibition of <scp>DNA</scp> methyltransferase 1

Abstract

Significantly 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.