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 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.

Mitochondrial Deoxyguanosine Kinase Regulates NAD+ Biogenesis Independent of Mitochondria Complex I Activity

“…We have previously shown frequent overexpression of DGUOK in lung adenocarcinoma and close association of elevated expression of DGUOK with tumor progression and patient survival (4). Knockout of the DGUOK in H1650 cells significantly inhibited cell migration and invasion ( Figures 5A-D).…”

“…We have recently reported that DGUOK overexpression promotes lung adenocarcinoma progression (4). Loss of DGUOK significantly induced mtDNA deletion and inhibited mitochondria complex I activity.…”

“…Mutations in the DGUOK led to mitochondrial DNA (mtDNA) depletion typically in the liver and brain, causing a hepatocerebral phenotype (3). We have previously shown that DGUOK was frequently overexpressed in lung adenocarcinoma and aberrant expression of DGUOK correlated with tumor progression and patient overall survival (4). However, the role and mechanism of DGUOK in lung cancer still poorly understood.…”

<p>Tobacco Smoke Plays an Important Role in Initiation and Development of Lung Cancer by Promoting the Characteristics of Cancer Stem Cells</p>

“…12 CSCs are resistant to conventional chemotherapy and radiation therapy, and can remain dormant for many years before cancer initiation, metastases and relapses. 13 Some previous studies showed that the critical role of CSCs in initiation and development of lung cancer, liver cancer, breast cancer, head and neck squamous cell carcinomas, pancreatic cancer and glioblastoma. [14][15][16][17][18][19] Lung CSCs are considered as the cancer initiating and maintaining cells of lung cancer.…”

“…15 Lin et al reported that lung CSCs are responsible for lung cancer initiation and local or metastatic recurrence, the mitochondrial deoxyguanosine kinase is required for CSCs stemness in lung adenocarcinoma. 13 Wang et al investigated that arsenic and BaP co-exposure produce CSC-like cells and promote the occurrence of lung cancer. 20 Hsu et al reported that lung CSCs confer tumorigenesis and resistance to standard treatment in lung cancer, targeting the upregulated glycolysis and its associated downstream pathways may be the novel strategies for eliminating CSCs and the better prognosis of cancer.…”