UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes
Background: Little is known about whether UVB can directly influence epigenetic regulatory pathways to induce cutaneous squamous cell carcinoma (CSCC). This study aimed to identify epigenetic-regulated signalling pathways through global methylation and gene expression profiling and to elucidate thei...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-07-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420302103 |
| _version_ | 1819037385015427072 |
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| author | Liming Li Fengjuan Li Yudong Xia Xueyuan Yang Qun Lv Fang Fang Qiang Wang Wenbo Bu Yan Wang Ke Zhang Yi Wu Junfang Shen Mingjun Jiang |
| author_facet | Liming Li Fengjuan Li Yudong Xia Xueyuan Yang Qun Lv Fang Fang Qiang Wang Wenbo Bu Yan Wang Ke Zhang Yi Wu Junfang Shen Mingjun Jiang |
| author_sort | Liming Li |
| collection | DOAJ |
| description | Background: Little is known about whether UVB can directly influence epigenetic regulatory pathways to induce cutaneous squamous cell carcinoma (CSCC). This study aimed to identify epigenetic-regulated signalling pathways through global methylation and gene expression profiling and to elucidate their function in CSCC development. Methods: Global DNA methylation profiling by reduced representation bisulfite sequencing (RRBS) and genome-wide gene expression analysis by RNA sequencing (RNA-seq) in eight pairs of matched CSCC and adjacent normal skin tissues were used to investigate the potential candidate gene(s). Clinical samples, animal models, cell lines, and UVB irradiation were applied to validate the mechanism and function of the genes of interest. Findings: We identified the downregulation of the TGF-β/BMP-SMAD-ID4 signalling pathway in CSCC and increased methylation of inhibitor of DNA binding/differentiation 4 (ID4). In normal human and mouse skin tissues and cutaneous cell lines, UVB exposure induced ID4 DNA methylation, upregulated DNMT1 and downregulated ten-eleven translocation (TETs). Similarly, we detected the upregulation of DNMT1 and downregulation of TETs accompanying ID4 DNA methylation in CSCC tissues. Silencing of DNMT1 and overexpression of TET1 and TET2 in A431 and Colo16 cells led to increased ID4 expression. Finally, we showed that overexpression of ID4 reduced cell proliferation, migration, and invasion, and increased apoptosis in CSCC cell lines and reduced tumourigenesis in mouse models. Interpretation: The results indicate that ID4 is downregulated by UVB irradiation via DNA methylation. ID4 acts as a tumour suppressor gene in CSCC development. Funding: CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-3-021, 2017-I2M-1-017), the Natural Science Foundation of Jiangsu Province (BK20191136), and the Fundamental Research Funds for the Central Universities (3332019104). |
| first_indexed | 2024-12-21T08:20:34Z |
| format | Article |
| id | doaj.art-9ee7b9422cef496a812069b561de628c |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-21T08:20:34Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-9ee7b9422cef496a812069b561de628c2022-12-21T19:10:27ZengElsevierEBioMedicine2352-39642020-07-0157102835UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymesLiming Li0Fengjuan Li1Yudong Xia2Xueyuan Yang3Qun Lv4Fang Fang5Qiang Wang6Wenbo Bu7Yan Wang8Ke Zhang9Yi Wu10Junfang Shen11Mingjun Jiang12Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaMethylGene Tech Co., Ltd. Guangzhou, Guangdong 510000, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, ChinaWest China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, ChinaMethylGene Tech Co., Ltd. Guangzhou, Guangdong 510000, ChinaInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu 210042, China; Corresponding author.Background: Little is known about whether UVB can directly influence epigenetic regulatory pathways to induce cutaneous squamous cell carcinoma (CSCC). This study aimed to identify epigenetic-regulated signalling pathways through global methylation and gene expression profiling and to elucidate their function in CSCC development. Methods: Global DNA methylation profiling by reduced representation bisulfite sequencing (RRBS) and genome-wide gene expression analysis by RNA sequencing (RNA-seq) in eight pairs of matched CSCC and adjacent normal skin tissues were used to investigate the potential candidate gene(s). Clinical samples, animal models, cell lines, and UVB irradiation were applied to validate the mechanism and function of the genes of interest. Findings: We identified the downregulation of the TGF-β/BMP-SMAD-ID4 signalling pathway in CSCC and increased methylation of inhibitor of DNA binding/differentiation 4 (ID4). In normal human and mouse skin tissues and cutaneous cell lines, UVB exposure induced ID4 DNA methylation, upregulated DNMT1 and downregulated ten-eleven translocation (TETs). Similarly, we detected the upregulation of DNMT1 and downregulation of TETs accompanying ID4 DNA methylation in CSCC tissues. Silencing of DNMT1 and overexpression of TET1 and TET2 in A431 and Colo16 cells led to increased ID4 expression. Finally, we showed that overexpression of ID4 reduced cell proliferation, migration, and invasion, and increased apoptosis in CSCC cell lines and reduced tumourigenesis in mouse models. Interpretation: The results indicate that ID4 is downregulated by UVB irradiation via DNA methylation. ID4 acts as a tumour suppressor gene in CSCC development. Funding: CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-3-021, 2017-I2M-1-017), the Natural Science Foundation of Jiangsu Province (BK20191136), and the Fundamental Research Funds for the Central Universities (3332019104).http://www.sciencedirect.com/science/article/pii/S2352396420302103Cutaneous squamous cell carcinomaUltraviolet raysDNA (cytosine-5-)-methyltransferaseDNA-binding proteinsTen-eleven translocationMethylation |
| spellingShingle | Liming Li Fengjuan Li Yudong Xia Xueyuan Yang Qun Lv Fang Fang Qiang Wang Wenbo Bu Yan Wang Ke Zhang Yi Wu Junfang Shen Mingjun Jiang UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes EBioMedicine Cutaneous squamous cell carcinoma Ultraviolet rays DNA (cytosine-5-)-methyltransferase DNA-binding proteins Ten-eleven translocation Methylation |
| title | UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes |
| title_full | UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes |
| title_fullStr | UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes |
| title_full_unstemmed | UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes |
| title_short | UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes |
| title_sort | uvb induces cutaneous squamous cell carcinoma progression by de novo id4 methylation via methylation regulating enzymes |
| topic | Cutaneous squamous cell carcinoma Ultraviolet rays DNA (cytosine-5-)-methyltransferase DNA-binding proteins Ten-eleven translocation Methylation |
| url | http://www.sciencedirect.com/science/article/pii/S2352396420302103 |
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