Research Papers:

LKB1 is a DNA damage response protein that regulates cellular sensitivity to PARP inhibitors

Yi-Shu Wang, Jianfeng Chen, Fengmei Cui, Huibo Wang, Shuai Wang, Wei Hang, Qinghua Zeng, Cheng-Shi Quan, Ying-Xian Zhai, Jian-Wei Wang, Xiang-Feng Shen, Yong-Ping Jian, Rui-Xun Zhao, Kaitlin D. Werle, Rutao Cui, Jiyong Liang, Yu-Lin Li and Zhi-Xiang Xu _

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Oncotarget. 2016; 7:73389-73401. https://doi.org/10.18632/oncotarget.12334

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Yi-Shu Wang1,*, Jianfeng Chen2,*, Fengmei Cui2,*, Huibo Wang2, Shuai Wang2, Wei Hang2, Qinghua Zeng1,2, Cheng-Shi Quan1, Ying-Xian Zhai1, Jian-Wei Wang1, Xiang-Feng Shen1, Yong-Ping Jian1, Rui-Xun Zhao2, Kaitlin D. Werle2, Rutao Cui3, Jiyong Liang4, Yu-Lin Li1, Zhi-Xiang Xu1,2

1Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China

2Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA

3Department of Pharmacology and Experimental Therapeutics, Boston University, School of Medicine, Boston, MA 02118, USA

4Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA

*These authors contributed equally to this work

Correspondence to:

Zhi-Xiang Xu, email: [email protected]

Yu-Lin Li, email: [email protected]

Keywords: DNA damage, homologous recombination, LKB1, sensitization, PARP inhibitor

Received: June 29, 2016     Accepted: September 17, 2016     Published: September 29, 2016


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), γ-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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