UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer
As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1–V4),...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383523000576 |
| _version_ | 1797823769126895616 |
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| author | Shuye Lin Hanli Xu Lin Qin Mengdi Pang Ziyu Wang Meng Gu Lishu Zhang Cong Zhao Xuefeng Hao Zhiyun Zhang Weimin Ding Jianke Ren Jiaqiang Huang |
| author_facet | Shuye Lin Hanli Xu Lin Qin Mengdi Pang Ziyu Wang Meng Gu Lishu Zhang Cong Zhao Xuefeng Hao Zhiyun Zhang Weimin Ding Jianke Ren Jiaqiang Huang |
| author_sort | Shuye Lin |
| collection | DOAJ |
| description | As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1–V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2′-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1–MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies. |
| first_indexed | 2024-03-13T10:27:53Z |
| format | Article |
| id | doaj.art-5faaba36d4ed4623a59063daac58d8c6 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-03-13T10:27:53Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-5faaba36d4ed4623a59063daac58d8c62023-05-19T04:45:27ZengElsevierActa Pharmaceutica Sinica B2211-38352023-05-0113520862106UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancerShuye Lin0Hanli Xu1Lin Qin2Mengdi Pang3Ziyu Wang4Meng Gu5Lishu Zhang6Cong Zhao7Xuefeng Hao8Zhiyun Zhang9Weimin Ding10Jianke Ren11Jiaqiang Huang12Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaCollege of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing 100044, ChinaDepartment of Endoscopic Diagnosis and Treatment, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaCollege of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing 100044, ChinaCancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaCancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaCancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaCancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaCancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaCancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaDepartment of Endoscopic Diagnosis and Treatment, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, ChinaCAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaCancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, China; College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing 100044, China; Corresponding author.As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1–V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2′-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1–MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies.http://www.sciencedirect.com/science/article/pii/S2211383523000576Lung cancerIntratumor heterogeneitySplice variantsIntragenic CpG methylationProtease serine 3Myeloid zinc finger 1 |
| spellingShingle | Shuye Lin Hanli Xu Lin Qin Mengdi Pang Ziyu Wang Meng Gu Lishu Zhang Cong Zhao Xuefeng Hao Zhiyun Zhang Weimin Ding Jianke Ren Jiaqiang Huang UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer Acta Pharmaceutica Sinica B Lung cancer Intratumor heterogeneity Splice variants Intragenic CpG methylation Protease serine 3 Myeloid zinc finger 1 |
| title | UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer |
| title_full | UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer |
| title_fullStr | UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer |
| title_full_unstemmed | UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer |
| title_short | UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer |
| title_sort | uhrf1 dnmt1 mzf1 axis modulated intragenic site specific cpgi methylation confers divergent expression and opposing functions of prss3 isoforms in lung cancer |
| topic | Lung cancer Intratumor heterogeneity Splice variants Intragenic CpG methylation Protease serine 3 Myeloid zinc finger 1 |
| url | http://www.sciencedirect.com/science/article/pii/S2211383523000576 |
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