Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma
Abstract Background Considering the increase in the proportion of lung adenocarcinoma (LUAD) cases among all lung cancers and its considerable contribution to cancer‐related deaths worldwide, we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-06-01
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| Series: | Cancer Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cac2.12155 |
| _version_ | 1818646294158114816 |
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| author | Quanli Zhang Run Shi Yongkang Bai Lijuan Meng Jingwen Hu Hongyu Zhu Tongyan Liu Xiaomeng De Siwei Wang Jie Wang Lin Xu Guoren Zhou Rong Yin |
| author_facet | Quanli Zhang Run Shi Yongkang Bai Lijuan Meng Jingwen Hu Hongyu Zhu Tongyan Liu Xiaomeng De Siwei Wang Jie Wang Lin Xu Guoren Zhou Rong Yin |
| author_sort | Quanli Zhang |
| collection | DOAJ |
| description | Abstract Background Considering the increase in the proportion of lung adenocarcinoma (LUAD) cases among all lung cancers and its considerable contribution to cancer‐related deaths worldwide, we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD. Methods The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) data were combined, and a promising risk biomarker called meiotic nuclear divisions 1 (MND1) was selectively acquired. Cell viability assays and subcutaneous xenograft models were used to validate the oncogenic role of MND1 in LUAD cell proliferation and tumor growth. A series of assays, including mass spectrometry, co‐immunoprecipitation (Co‐IP), and chromatin immunoprecipitation (ChIP), were performed to explore the underlying mechanism. Results MND1 up‐regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis. In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle. The results of the Co‐IP, ChIP and dual‐luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel‐like factor 6 (KLF6), and thereby protecting E2F transcription factor 1 (E2F1) from KLF6‐induced transcriptional repression. Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner. Conclusions MND1, KLF6, and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD. MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients. |
| first_indexed | 2024-12-17T00:44:21Z |
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| id | doaj.art-cce4e2b2feed46d48c19b5cb83445daf |
| institution | Directory Open Access Journal |
| issn | 2523-3548 |
| language | English |
| last_indexed | 2024-12-17T00:44:21Z |
| publishDate | 2021-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Communications |
| spelling | doaj.art-cce4e2b2feed46d48c19b5cb83445daf2022-12-21T22:09:56ZengWileyCancer Communications2523-35482021-06-0141649251010.1002/cac2.12155Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinomaQuanli Zhang0Run Shi1Yongkang Bai2Lijuan Meng3Jingwen Hu4Hongyu Zhu5Tongyan Liu6Xiaomeng De7Siwei Wang8Jie Wang9Lin Xu10Guoren Zhou11Rong Yin12Department of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaFaculty of Medicine Ludwig‐Maximilians‐Universität (LMU) München München Bayern D‐80539 GermanyDepartment of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaDepartment of Geriatric Oncology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu 210009 P. R. ChinaDepartment of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaDepartment of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaDepartment of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaDepartment of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaDepartment of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaDepartment of Scientific Research, Jiangsu Cancer Hospital & the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Institute of Cancer Research Jiangsu Key Laboratory of Molecular and Translational Cancer Research Nanjing Jiangsu 210009 P. R. ChinaDepartment of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaDepartment of Oncology Jiangsu Cancer Hospital & the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Institute of Cancer Research Nanjing Jiangsu 210009 P. R. ChinaDepartment of Thoracic Surgery, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Jiangsu 210009 P. R. ChinaAbstract Background Considering the increase in the proportion of lung adenocarcinoma (LUAD) cases among all lung cancers and its considerable contribution to cancer‐related deaths worldwide, we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD. Methods The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) data were combined, and a promising risk biomarker called meiotic nuclear divisions 1 (MND1) was selectively acquired. Cell viability assays and subcutaneous xenograft models were used to validate the oncogenic role of MND1 in LUAD cell proliferation and tumor growth. A series of assays, including mass spectrometry, co‐immunoprecipitation (Co‐IP), and chromatin immunoprecipitation (ChIP), were performed to explore the underlying mechanism. Results MND1 up‐regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis. In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle. The results of the Co‐IP, ChIP and dual‐luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel‐like factor 6 (KLF6), and thereby protecting E2F transcription factor 1 (E2F1) from KLF6‐induced transcriptional repression. Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner. Conclusions MND1, KLF6, and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD. MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients.https://doi.org/10.1002/cac2.12155cell cyclecisplatin resistanceE2F transcription factor 1 (E2F1)Kruppel‐like factor 6 (KLF6)lung adenocarcinomameiotic nuclear divisions 1 (MND1) |
| spellingShingle | Quanli Zhang Run Shi Yongkang Bai Lijuan Meng Jingwen Hu Hongyu Zhu Tongyan Liu Xiaomeng De Siwei Wang Jie Wang Lin Xu Guoren Zhou Rong Yin Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma Cancer Communications cell cycle cisplatin resistance E2F transcription factor 1 (E2F1) Kruppel‐like factor 6 (KLF6) lung adenocarcinoma meiotic nuclear divisions 1 (MND1) |
| title | Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma |
| title_full | Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma |
| title_fullStr | Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma |
| title_full_unstemmed | Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma |
| title_short | Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma |
| title_sort | meiotic nuclear divisions 1 mnd1 fuels cell cycle progression by activating a klf6 e2f1 positive feedback loop in lung adenocarcinoma |
| topic | cell cycle cisplatin resistance E2F transcription factor 1 (E2F1) Kruppel‐like factor 6 (KLF6) lung adenocarcinoma meiotic nuclear divisions 1 (MND1) |
| url | https://doi.org/10.1002/cac2.12155 |
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