Hypomethylation of <i>CLDN4</i> 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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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/12/6516 |
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| author | Fumisato Maesaka Masaomi Kuwada Shohei Horii Shingo Kishi Rina Fujiwara-Tani Shiori Mori Kiyomu Fujii Takuya Mori Hitoshi Ohmori Takuya Owari Makito Miyake Yasushi Nakai Nobumichi Tanaka Ujjal Kumar Bhawal Yi Luo Masuo Kondoh Kiyohide Fujimoto Hiroki Kuniyasu |
| author_facet | Fumisato Maesaka Masaomi Kuwada Shohei Horii Shingo Kishi Rina Fujiwara-Tani Shiori Mori Kiyomu Fujii Takuya Mori Hitoshi Ohmori Takuya Owari Makito Miyake Yasushi Nakai Nobumichi Tanaka Ujjal Kumar Bhawal Yi Luo Masuo Kondoh Kiyohide Fujimoto Hiroki Kuniyasu |
| author_sort | Fumisato Maesaka |
| collection | DOAJ |
| description | 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 <i>CLDN4</i> 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. <i>CLDN4</i> promoter DNA methylation is expected to be a novel indicator of BUC malignant phenotype and a new therapeutic target. |
| first_indexed | 2024-03-09T23:35:28Z |
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| id | doaj.art-c8f4f1fd4d964795a7da00a51cfa6db3 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:35:28Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c8f4f1fd4d964795a7da00a51cfa6db32023-11-23T17:02:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312651610.3390/ijms23126516Hypomethylation of <i>CLDN4</i> Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder CancerFumisato Maesaka0Masaomi Kuwada1Shohei Horii2Shingo Kishi3Rina Fujiwara-Tani4Shiori Mori5Kiyomu Fujii6Takuya Mori7Hitoshi Ohmori8Takuya Owari9Makito Miyake10Yasushi Nakai11Nobumichi Tanaka12Ujjal Kumar Bhawal13Yi Luo14Masuo Kondoh15Kiyohide Fujimoto16Hiroki Kuniyasu17Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Urology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, JapanDepartment of Urology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, JapanDepartment of Urology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, JapanDepartment of Urology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanJiangsu Province Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, ChinaDrug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, 6-1 Yamadaoka, Suita 565-0871, Osaka, JapanDepartment of Urology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, JapanDepartment of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanThe 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 <i>CLDN4</i> 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. <i>CLDN4</i> promoter DNA methylation is expected to be a novel indicator of BUC malignant phenotype and a new therapeutic target.https://www.mdpi.com/1422-0067/23/12/6516claudin-4promoter methylationbladder cancerstemnessnon-tight junction claudin |
| spellingShingle | Fumisato Maesaka Masaomi Kuwada Shohei Horii Shingo Kishi Rina Fujiwara-Tani Shiori Mori Kiyomu Fujii Takuya Mori Hitoshi Ohmori Takuya Owari Makito Miyake Yasushi Nakai Nobumichi Tanaka Ujjal Kumar Bhawal Yi Luo Masuo Kondoh Kiyohide Fujimoto Hiroki Kuniyasu Hypomethylation of <i>CLDN4</i> Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer International Journal of Molecular Sciences claudin-4 promoter methylation bladder cancer stemness non-tight junction claudin |
| title | Hypomethylation of <i>CLDN4</i> Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer |
| title_full | Hypomethylation of <i>CLDN4</i> Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer |
| title_fullStr | Hypomethylation of <i>CLDN4</i> Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer |
| title_full_unstemmed | Hypomethylation of <i>CLDN4</i> Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer |
| title_short | Hypomethylation of <i>CLDN4</i> Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer |
| title_sort | hypomethylation of i cldn4 i gene promoter is associated with malignant phenotype in urinary bladder cancer |
| topic | claudin-4 promoter methylation bladder cancer stemness non-tight junction claudin |
| url | https://www.mdpi.com/1422-0067/23/12/6516 |
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