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

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 hyp...

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Published in:International journal of molecular sciences 2022-06, Vol.23 (12), p.6516
Main Authors: Maesaka, Fumisato, Kuwada, Masaomi, Horii, Shohei, Kishi, Shingo, Fujiwara-Tani, Rina, Mori, Shiori, Fujii, Kiyomu, Mori, Takuya, Ohmori, Hitoshi, Owari, Takuya, Miyake, Makito, Nakai, Yasushi, Tanaka, Nobumichi, Bhawal, Ujjal Kumar, Luo, Yi, Kondoh, Masuo, Fujimoto, Kiyohide, Kuniyasu, Hiroki
Format: Article
Language:English
Subjects:
Apoptosis
Bladder
Bladder cancer
Cell proliferation
claudin-4
CpG islands
Deoxyribonucleic acid
DNA
DNA methylation
Drug resistance
Epigenetics
Gastric cancer
Gene expression
Genotype & phenotype
Growth factors
Mesenchyme
Metastases
Metastasis
non-tight junction claudin
Ovarian cancer
Phenotypes
Phosphorylation
promoter methylation
Proteins
stemness
Therapeutic targets
Tumors
Urinary bladder
Urothelial carcinoma
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23126516