Hypomethylation of CLDN4 Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer

International Journal of Molecular Sciences

Rina Fujiwara-Tani¹  Hiroki Kuniyasu¹  Fumisato Maesaka¹  Ujjal Kumar Bhawal¹  Hitoshi Ohmori¹  Shiori Mori¹  Shohei Horii¹  Masaomi Kuwada¹  Shingo Kishi¹  Kiyomu Fujii¹  Takuya Mori¹  Kiyohide Fujimoto²  Nobumichi Tanaka²  Yasushi Nakai²  Takuya Owari²  Makito Miyake²  Masuo Kondoh³  Yi Luo⁴ 

[1] Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan;Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan;Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, 6-1 Yamadaoka, Suita 565-0871, Osaka, Japan;Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China;

关键词: claudin-4;    promoter methylation;    bladder cancer;    stemness;    non-tight junction claudin;   

DOI  :  10.3390/ijms23126516

来源: DOAJ

【 摘 要 】

The tight junction (TJ) protein claudin-4 (CLDN4) is overexpressed in bladder urothelial carcinoma (BUC) and correlates with cancer progression. However, the mechanism of CLDN4 upregulation and promotion of malignant phenotype is not clear. Here, we analyzed 157 cases of BUC and investigated the hypomethylation of CpG island in the CLDN4 promoter DNA and its correlation with cancer progression. In hypomethylated cases, CLDN4 expression, cell proliferation, stemness, and epithelial-mesenchymal transition were increased. Treatment of three human BUC cell lines with the demethylating agent aza-2′-deoxycytidine (AZA) led to excessive CLDN4 expression, and, specifically, to an increase in CLDN4 monomer that is not integrated into the TJ. The TJ-unintegrated CLDN4 was found to bind integrin β1 and increase stemness, drug resistance, and metastatic ability of the cells as well as show an anti-apoptosis effect likely via FAK phosphorylation, which reduces upon knockdown of CLDN4. Thus, CLDN4 is overexpressed in BUC by an epigenetic mechanism and the high expression enhances the malignant phenotype of BUC via increased levels of TJ-unintegrated CLDN4. CLDN4 promoter DNA methylation is expected to be a novel indicator of BUC malignant phenotype and a new therapeutic target.

【 授权许可】

Unknown