CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma
Abstract Currently, there is still a lack of novel and effective drug targets to improve the prognosis of hepatocellular carcinoma (HCC). Additionally, the role of CHEK2 in HCC has not been reported yet. The eQTLgen database and two HCC Genome-Wide Association Study (GWAS) datasets (ieu-b-4953, ICD1...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01777-4 |
| _version_ | 1797350156698386432 |
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| author | Yuyan Chen Zhengyi Zhu Xingyu Wu Hui Li Wenxian Guan Haozhen Ren |
| author_facet | Yuyan Chen Zhengyi Zhu Xingyu Wu Hui Li Wenxian Guan Haozhen Ren |
| author_sort | Yuyan Chen |
| collection | DOAJ |
| description | Abstract Currently, there is still a lack of novel and effective drug targets to improve the prognosis of hepatocellular carcinoma (HCC). Additionally, the role of CHEK2 in HCC has not been reported yet. The eQTLgen database and two HCC Genome-Wide Association Study (GWAS) datasets (ieu-b-4953, ICD10 C22.0) were used to find the drug target: CHEK2. Next, Colony, Edu, β-gal, and cell cycle analysis were facilitated to evaluate the role of CHEK2 knockout in HCC. In addition, Nultin-3 was added to evaluate the apoptosis of TP53-mutated HCC cells with CHEK2 knockout. Furthermore, MitoSox, electron microscopy, mitochondrial ATP, and NADH+/NADH levels were assessed in the CHEK2 knockout HCC cells with or without Metformin. Finally, cell-derived tumor xenograft was used to evaluate the role of CHEK2 knockout in vivo. We initially identified a potential drug target, CHEK2, through GWAS data analysis. Furthermore, we observed a significant upregulation of CHEK2 expression in HCC, which was found to be correlated with a poor prognosis. Subsequently, the results indicated that knocking out CHEK2 selectively affects the proliferation, cell cycle, senescence, and apoptosis of TP53-mutant HCC cells. Additionally, the introduction of Nultin-3 further intensified the functional impact on TP53-mutant cells. Then ClusterProfiler results showed high CHEK2 and TP53 mutation group was positively enriched in the mitochondrial ATP pathway. Then we used MitoSox, electron microscopy, mitochondrial ATP, and NADH + /NADH assay and found knockout of CHECK could induce the ATP pathway to inhibit the growth of HCC. Our research introduces a novel drug target for TP53-mutant HCC cells via mitochondrial ATP, addressing the limitation of Nultin-3 as a standalone treatment that does not induce tumor cell death. |
| first_indexed | 2024-03-08T12:40:43Z |
| format | Article |
| id | doaj.art-c3fb4c1f50c047fe8501b170fa93ccae |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-08T12:40:43Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-c3fb4c1f50c047fe8501b170fa93ccae2024-01-21T12:10:43ZengNature Publishing GroupCell Death Discovery2058-77162024-01-0110111210.1038/s41420-023-01777-4CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinomaYuyan Chen0Zhengyi Zhu1Xingyu Wu2Hui Li3Wenxian Guan4Haozhen Ren5Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDivision of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDivision of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDivision of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityAbstract Currently, there is still a lack of novel and effective drug targets to improve the prognosis of hepatocellular carcinoma (HCC). Additionally, the role of CHEK2 in HCC has not been reported yet. The eQTLgen database and two HCC Genome-Wide Association Study (GWAS) datasets (ieu-b-4953, ICD10 C22.0) were used to find the drug target: CHEK2. Next, Colony, Edu, β-gal, and cell cycle analysis were facilitated to evaluate the role of CHEK2 knockout in HCC. In addition, Nultin-3 was added to evaluate the apoptosis of TP53-mutated HCC cells with CHEK2 knockout. Furthermore, MitoSox, electron microscopy, mitochondrial ATP, and NADH+/NADH levels were assessed in the CHEK2 knockout HCC cells with or without Metformin. Finally, cell-derived tumor xenograft was used to evaluate the role of CHEK2 knockout in vivo. We initially identified a potential drug target, CHEK2, through GWAS data analysis. Furthermore, we observed a significant upregulation of CHEK2 expression in HCC, which was found to be correlated with a poor prognosis. Subsequently, the results indicated that knocking out CHEK2 selectively affects the proliferation, cell cycle, senescence, and apoptosis of TP53-mutant HCC cells. Additionally, the introduction of Nultin-3 further intensified the functional impact on TP53-mutant cells. Then ClusterProfiler results showed high CHEK2 and TP53 mutation group was positively enriched in the mitochondrial ATP pathway. Then we used MitoSox, electron microscopy, mitochondrial ATP, and NADH + /NADH assay and found knockout of CHECK could induce the ATP pathway to inhibit the growth of HCC. Our research introduces a novel drug target for TP53-mutant HCC cells via mitochondrial ATP, addressing the limitation of Nultin-3 as a standalone treatment that does not induce tumor cell death.https://doi.org/10.1038/s41420-023-01777-4 |
| spellingShingle | Yuyan Chen Zhengyi Zhu Xingyu Wu Hui Li Wenxian Guan Haozhen Ren CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma Cell Death Discovery |
| title | CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma |
| title_full | CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma |
| title_fullStr | CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma |
| title_full_unstemmed | CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma |
| title_short | CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma |
| title_sort | chek2 knockout is a therapeutic target for tp53 mutated hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41420-023-01777-4 |
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