Inhibition of bladder cancer invasion by Sp1-mediated BTG2 expression via inhibition of DNA methyltransferase 1
Inhibition of bladder cancer invasion by Sp1-mediated BTG2 expression via inhibition of DNA methyltransferase 1
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DOI：
10.1111/febs.13099
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发表时间：
2014-12-01
期刊：
影响因子：
5.4
通讯作者：
Lim, In Kyoung
中科院分区：
文献类型：
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作者：
Devanand, Preethi;Kim, Sun Il;Lim, In Kyoung
在人类肌层浸润性膀胱癌 (MIBC) 中观察到 B 细胞易位基因 2 (BTG2) 的内源性表达显着低于匹配的正常组织和非肌层浸润性膀胱癌 (NMIBC)。在 MIBC 中，BTG2 表达与 DNA 甲基转移酶 DNMT1 和 DNMT3a 的表达增加呈负相关，但在 NMIBC 中则不然，这表明 BTG2 表达在膀胱癌肌肉侵袭中具有潜在作用。超过90%的肿瘤组织在BTG2基因的CpG岛处显示出强甲基化，而正常组织中没有甲基化，这意味着BTG2表达在膀胱癌发生过程中受到表观遗传调控。通过使用 EJ 膀胱癌细胞和去甲基化剂地西他滨，通过 CpG 岛的修饰抑制 DNMT1 表达，BTG2 的转录被上调。 DNMT1与BTG2基因结合进一步通过染色质重塑（例如H3K9二甲基化和H3K4三甲基化以及Sp1激活）调节BTG2表达。诱导的 BTG2 表达显着降低了 EJ 细胞的肿瘤发生和侵袭性，同时诱导了 G2/M 期停滞。这些结果证明了 BTG2/TIS21/PC3 基因在膀胱癌进展中的重要作用，并表明 BTG2/TIS21/PC3 是预防人类膀胱癌肌肉侵袭的有前途的表观遗传靶标。
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/PC3gene in the progression of bladder cancers, and suggest that BTG2/TIS21/PC3is a promising epigenetic target for prevention of muscle invasion in human bladder cancers.