The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma
Abstract The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate‐limiting enzyme in this pathway. Here, we investigated the role of...
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Springer Nature
2019-10-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201910849 |
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| author | Shengchen Lin Chongbiao Huang Jianwei Sun Oana Bollt Xiuchao Wang Eric Martine Jiaxin Kang Matthew D Taylor Bin Fang Pankaj K Singh John Koomen Jihui Hao Shengyu Yang |
| author_facet | Shengchen Lin Chongbiao Huang Jianwei Sun Oana Bollt Xiuchao Wang Eric Martine Jiaxin Kang Matthew D Taylor Bin Fang Pankaj K Singh John Koomen Jihui Hao Shengyu Yang |
| author_sort | Shengchen Lin |
| collection | DOAJ |
| description | Abstract The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate‐limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self‐renewal of lung cancer stem‐like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self‐renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self‐renewal through AMPK‐YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK‐mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline‐inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC‐mediated therapy resistance and metastatic recurrence. |
| format | Article |
| id | doaj-art-2b1bcd46ad9241968307c033ac2143a2 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-2b1bcd46ad9241968307c033ac2143a22025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-10-01111212010.15252/emmm.201910849The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinomaShengchen Lin0Chongbiao Huang1Jianwei Sun2Oana Bollt3Xiuchao Wang4Eric Martine5Jiaxin Kang6Matthew D Taylor7Bin Fang8Pankaj K Singh9John Koomen10Jihui Hao11Shengyu Yang12Department of Cellular and Molecular Physiology, The Pennsylvania State University College of MedicineKey Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for CancerDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of MedicineDepartment of Surgery, The Pennsylvania State University College of MedicineDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of MedicineDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of MedicineDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of MedicineDepartment of Surgery, The Pennsylvania State University College of MedicineDepartment of Molecular Oncology, Proteomics & Metabolomics Core, H. Lee Moffitt Cancer CenterDepartment of Pathology and Microbiology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical CenterDepartment of Molecular Oncology, Proteomics & Metabolomics Core, H. Lee Moffitt Cancer CenterKey Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for CancerDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of MedicineAbstract The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate‐limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self‐renewal of lung cancer stem‐like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self‐renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self‐renewal through AMPK‐YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK‐mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline‐inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC‐mediated therapy resistance and metastatic recurrence.https://doi.org/10.15252/emmm.201910849cancer stem cellDGUOKlung cancermetastasismitochondria |
| spellingShingle | Shengchen Lin Chongbiao Huang Jianwei Sun Oana Bollt Xiuchao Wang Eric Martine Jiaxin Kang Matthew D Taylor Bin Fang Pankaj K Singh John Koomen Jihui Hao Shengyu Yang The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma EMBO Molecular Medicine cancer stem cell DGUOK lung cancer metastasis mitochondria |
| title | The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma |
| title_full | The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma |
| title_fullStr | The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma |
| title_full_unstemmed | The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma |
| title_short | The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma |
| title_sort | mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma |
| topic | cancer stem cell DGUOK lung cancer metastasis mitochondria |
| url | https://doi.org/10.15252/emmm.201910849 |
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