The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere10849
JournalEMBO Molecular Medicine
Volume11
Issue number12
DOIs
StatePublished - Dec 1 2019

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deoxyguanosine kinase
Neoplastic Stem Cells
Neoplasms
Lung Neoplasms
AMP-Activated Protein Kinases
Clustered Regularly Interspaced Short Palindromic Repeats
Electron Transport Complex I
Doxycycline
Growth
Cell- and Tissue-Based Therapy
Adenocarcinoma of lung
Mitochondrial DNA
Homeostasis

Keywords

  • DGUOK
  • cancer stem cell
  • lung cancer
  • metastasis
  • mitochondria

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma. / Lin, Shengchen; Huang, Chongbiao; Sun, Jianwei; Bollt, Oana; Wang, Xiuchao; Martine, Eric; Kang, Jiaxin; Taylor, Matthew D.; Fang, Bin; Singh, Pankaj K.; Koomen, John; Hao, Jihui; Yang, Shengyu.

In: EMBO Molecular Medicine, Vol. 11, No. 12, e10849, 01.12.2019.

Research output: Contribution to journalArticle

Lin, S, Huang, C, Sun, J, Bollt, O, Wang, X, Martine, E, Kang, J, Taylor, MD, Fang, B, Singh, PK, Koomen, J, Hao, J & Yang, S 2019, 'The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma', EMBO Molecular Medicine, vol. 11, no. 12, e10849. https://doi.org/10.15252/emmm.201910849
Lin, Shengchen ; Huang, Chongbiao ; Sun, Jianwei ; Bollt, Oana ; Wang, Xiuchao ; Martine, Eric ; Kang, Jiaxin ; Taylor, Matthew D. ; Fang, Bin ; Singh, Pankaj K. ; Koomen, John ; Hao, Jihui ; Yang, Shengyu. / The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma. In: EMBO Molecular Medicine. 2019 ; Vol. 11, No. 12.
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