期刊
ONCOTARGET
卷 7, 期 45, 页码 73389-73401出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12334
关键词
DNA damage; homologous recombination; LKB1; sensitization; PARP inhibitor
资金
- National Cancer Institute [R01CA133053]
- Cervical Cancer SPORE Career Development Award from NCI [P50CA098252]
- Wendy Will Case Cancer Fund, Inc.
- National Natural Science Foundation of China [81271853, 81272243, 81573087]
- International S&T Cooperation Projects of Jilin Province, China [2016414023GH]
- Key S&T Research and Development Program of Jilin Province, China [20150204066SF]
Liver kinase B1 (LKB1) functions as a tumor suppressor encoded by STK11, a gene that mutated in Peutz-Jeghers syndrome and in sporadic cancers. Previous studies showed that LKB1 participates in IR- and ROS-induced DNA damage response (DDR). However, the impact of LKB1 mutations on targeted cancer therapy remains unknown. Herein, we demonstrated that LKB1 formed DNA damage-induced nuclear foci and co-localized with ataxia telangiectasia mutated kinase (ATM), gamma-H2AX, and breast cancer susceptibility 1 (BRCA1). ATM mediated LKB1 phosphorylation at Thr 363 following the exposure of cells to ionizing radiation (IR). LKB1 interacted with BRCA1, a downstream effector in DDR that is recruited to sites of DNA damage and functions directly in homologous recombination (HR) DNA repair. LKB1 deficient cells exhibited delayed DNA repair due to insufficient HR. Notably, LKB1 deficiency sensitized cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Thus, we have demonstrated a novel function of LKB1 in DNA damage response. Cancer cells lacking LKB1 are more susceptible to DNA damage-based therapy and, in particular, to drugs that further impair DNA repair, such as PARP inhibitors.
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