Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis
Background: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. Methods: A total of 696 U...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420300645 |
| _version_ | 1828750241982054400 |
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| author | Xin-Chun Zhao Gui-Zhen Wang Zhe-Sheng Wen Yong-Chun Zhou Qian Hu Bin Zhang Li-Wei Qu San-Hui Gao Jie Liu Liang Ma Yan-Fei Zhang Chen Zhang Hong Yu Da-Lin Zhang Min Wang Chang-Li Wang Yun-Chao Huang Zhi-hua Liu Yong Zhao Liang Chen Guang-Biao Zhou |
| author_facet | Xin-Chun Zhao Gui-Zhen Wang Zhe-Sheng Wen Yong-Chun Zhou Qian Hu Bin Zhang Li-Wei Qu San-Hui Gao Jie Liu Liang Ma Yan-Fei Zhang Chen Zhang Hong Yu Da-Lin Zhang Min Wang Chang-Li Wang Yun-Chao Huang Zhi-hua Liu Yong Zhao Liang Chen Guang-Biao Zhou |
| author_sort | Xin-Chun Zhao |
| collection | DOAJ |
| description | Background: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. Methods: A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo. Findings: We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation. Interpretation: These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs. Funding: National Key Research and Development Program of China, National Natural Science Foundation of China, and the CAMS Innovation Fund for Medical Sciences. Keywords: Lung cancer, Ubiquitin pathway genes, CDC34, EGFR, c-Cbl |
| first_indexed | 2024-12-10T20:35:11Z |
| format | Article |
| id | doaj.art-24484073cb9c461a9d071eb6d3df48f5 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-10T20:35:11Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-24484073cb9c461a9d071eb6d3df48f52022-12-22T01:34:33ZengElsevierEBioMedicine2352-39642020-03-0153Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesisXin-Chun Zhao0Gui-Zhen Wang1Zhe-Sheng Wen2Yong-Chun Zhou3Qian Hu4Bin Zhang5Li-Wei Qu6San-Hui Gao7Jie Liu8Liang Ma9Yan-Fei Zhang10Chen Zhang11Hong Yu12Da-Lin Zhang13Min Wang14Chang-Li Wang15Yun-Chao Huang16Zhi-hua Liu17Yong Zhao18Liang Chen19Guang-Biao Zhou20State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China; Cancer Institute, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, ChinaState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Medical Oncology Department, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, ChinaDepartment of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Kunming 650106, ChinaState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Beijing 100029, ChinaDepartment of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Beijing 100029, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaDepartment of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, ChinaDepartment of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Kunming 650106, ChinaState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, ChinaInstitute of Life and Health Engineering, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China; Corresponding author at: State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.Background: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. Methods: A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo. Findings: We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation. Interpretation: These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs. Funding: National Key Research and Development Program of China, National Natural Science Foundation of China, and the CAMS Innovation Fund for Medical Sciences. Keywords: Lung cancer, Ubiquitin pathway genes, CDC34, EGFR, c-Cblhttp://www.sciencedirect.com/science/article/pii/S2352396420300645 |
| spellingShingle | Xin-Chun Zhao Gui-Zhen Wang Zhe-Sheng Wen Yong-Chun Zhou Qian Hu Bin Zhang Li-Wei Qu San-Hui Gao Jie Liu Liang Ma Yan-Fei Zhang Chen Zhang Hong Yu Da-Lin Zhang Min Wang Chang-Li Wang Yun-Chao Huang Zhi-hua Liu Yong Zhao Liang Chen Guang-Biao Zhou Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis EBioMedicine |
| title | Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis |
| title_full | Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis |
| title_fullStr | Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis |
| title_full_unstemmed | Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis |
| title_short | Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis |
| title_sort | systematic identification of cdc34 that functions to stabilize egfr and promote lung carcinogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2352396420300645 |
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