Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells.
DNA double-strand breaks (DSBs) are traditionally associated with cancer through their abilities to cause chromosomal instabilities or gene mutations. Here we report a new class of self-inflicted DNA DSBs that can drive tumor growth irrespective of their effects on genomic stability. We discover a mechanism through which cancer cells cause DSBs in their own genome spontaneously independent of reactive oxygen species or replication stress. In this mechanism, low-level cytochrome c leakage from the mitochondria leads to sublethal activation of apoptotic caspases and nucleases, which causes DNA DSBs. In response to these spontaneous DNA DSBs, ATM, a key factor involved in DNA damage response, is constitutively activated. Activated ATM leads to activation of transcription factors NF-κB and STAT3, known drivers of tumor growth. Moreover, self-inflicted DNA DSB formation and ATM activation are important in sustaining the stemness of patient-derived glioma cells. In human tumor tissues, elevated levels of activated ATM correlate with poor patient survival. Self-inflicted DNA DSBs therefore are functionally important for maintaining the malignancy of cancer cells.
Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
Xinjian
X
Liu
Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
Fang
F
Li
Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, China.
Qian
Q
Huang
Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, China.
Zhengxiang
Z
Zhang
Department of Surgery, Shanghai General Branch Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200081, China.
Ling
L
Zhou
Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
Yu
Y
Deng
Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.|State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai JiaotongUniversity, Shanghai 200032, China.
Min
M
Zhou
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Donald E
DE
Fleenor
West China Second University Hospital, Sichuan University, Chengdu 610041, China.
He
H
Wang
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.|Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
Michael B
MB
Kastan
Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.|Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
Chuan-Yuan
CY
Li
D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
D018797:Cell Cycle Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D045304:Cytochromes c; D064007:Ataxia Telangiectasia Mutated Proteins