The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy
Abstract Background Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dyn...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-02-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-024-01513-0 |
| _version_ | 1797273853196500992 |
|---|---|
| author | Mei Zhou Limin Duan Jiangbin Chen Yumei Li Zhengrong Yin Siwei Song Yaqi Cao Ping Luo Fan Hu Guanghai Yang Juanjuan Xu Tingting Liao Yang Jin |
| author_facet | Mei Zhou Limin Duan Jiangbin Chen Yumei Li Zhengrong Yin Siwei Song Yaqi Cao Ping Luo Fan Hu Guanghai Yang Juanjuan Xu Tingting Liao Yang Jin |
| author_sort | Mei Zhou |
| collection | DOAJ |
| description | Abstract Background Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. Results In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. Conclusion In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment. Graphical Abstract |
| first_indexed | 2024-03-07T14:50:05Z |
| format | Article |
| id | doaj.art-ef77ede7b72c4464886802f6eaf66bc8 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-07T14:50:05Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-ef77ede7b72c4464886802f6eaf66bc82024-03-05T19:46:38ZengBMCCell Communication and Signaling1478-811X2024-02-0122112910.1186/s12964-024-01513-0The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapyMei Zhou0Limin Duan1Jiangbin Chen2Yumei Li3Zhengrong Yin4Siwei Song5Yaqi Cao6Ping Luo7Fan Hu8Guanghai Yang9Juanjuan Xu10Tingting Liao11Yang Jin12Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Translational Medicine Center, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyMedical Subcenter of HUST Analytical & Testing Center, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. Results In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. Conclusion In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment. Graphical Abstracthttps://doi.org/10.1186/s12964-024-01513-0Tumour cell cycleSHCBP1DNA-damaging agentsSynergistic target |
| spellingShingle | Mei Zhou Limin Duan Jiangbin Chen Yumei Li Zhengrong Yin Siwei Song Yaqi Cao Ping Luo Fan Hu Guanghai Yang Juanjuan Xu Tingting Liao Yang Jin The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy Cell Communication and Signaling Tumour cell cycle SHCBP1 DNA-damaging agents Synergistic target |
| title | The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy |
| title_full | The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy |
| title_fullStr | The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy |
| title_full_unstemmed | The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy |
| title_short | The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy |
| title_sort | dynamic role of nucleoprotein shcbp1 in the cancer cell cycle and its potential as a synergistic target for dna damaging agents in cancer therapy |
| topic | Tumour cell cycle SHCBP1 DNA-damaging agents Synergistic target |
| url | https://doi.org/10.1186/s12964-024-01513-0 |
| work_keys_str_mv | AT meizhou thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT liminduan thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT jiangbinchen thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT yumeili thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT zhengrongyin thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT siweisong thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT yaqicao thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT pingluo thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT fanhu thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT guanghaiyang thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT juanjuanxu thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT tingtingliao thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT yangjin thedynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT meizhou dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT liminduan dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT jiangbinchen dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT yumeili dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT zhengrongyin dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT siweisong dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT yaqicao dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT pingluo dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT fanhu dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT guanghaiyang dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT juanjuanxu dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT tingtingliao dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy AT yangjin dynamicroleofnucleoproteinshcbp1inthecancercellcycleanditspotentialasasynergistictargetfordnadamagingagentsincancertherapy |