Research Papers:

SIRT1 inhibition impairs non-homologous end joining DNA damage repair by increasing Ku70 acetylation in chronic myeloid leukemia cells

Wenjun Zhang, Haixia Wu, Meng Yang, Shiguang Ye, Liang Li, Hong Zhang, Jiong Hu, Xuguang Wang, Jun Xu and Aibin Liang _

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Oncotarget. 2016; 7:13538-13550. https://doi.org/10.18632/oncotarget.6455

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Wenjun Zhang1,*, Haixia Wu1,*, Meng Yang1,*, Shiguang Ye1, Liang Li1, Hong Zhang2, Jiong Hu3, Xuguang Wang4, Jun Xu5 and Aibin Liang1

1 Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, P.R. China

2 Department of Clinical Pharmacology, Tongji Hospital, Tongji University School of Medicine, Shanghai, P.R. China

3 Department of Hematology and Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China

4 Clinical Research Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong, P.R. China

5 East Hospital, Tongji University School of Medicine, Shanghai, P.R. China

* These authors have Contributed equally to this work

Correspondence to:

Xuguang Wang, email:

Jun Xu, email:

Aibin Liang, email:

Keywords: SIRT1, DNA damage repair, non-homologous end joining, Ku70

Received: May 13, 2015 Accepted: October 14, 2015 Published: December 03, 2015


Most chemotherapeutic agents for leukemia are DNA damaging agents. However, DNA lesions can be repaired by activities of DNA repair systems. Increasing evidence have shown that enhanced DNA damage repair capacity contributes to chemotherapy resistance in leukemia cells. Thus, targeting DNA repair mechanisms is a promising strategy for novel leukemia treatment. SIRT1 expressions were downregulated by lentivirus-delivered SIRT1 shRNA in myeloid leukemia cells. SIRT1 mRNA and protein levels were analyzed by real-time PCR and Western blot, respectively. Flow cytometry was carried out to analyze cell cycle progression, apoptosis and DNA damage repair efficiency. DNA damage levels were assessed by alkaline comet assay, and H2AX phosphorylation was analyzed by immunoblotting and immunofluorescence. A mouse leukemia model was established by transplanting lentivirus-infected K562 cells containing SIRT1 shRNA into sublethally irradiated NOD/SCID mice, and tumorigenesis was evaluated by detecting tumor weights and mice survival. SIRT1 expressions were upregulated in myeloid leukemic patients. Downregulation of SIRT1 by RNAi promoted etoposide-induced DNA damage in myeloid leukemia cells accompanied by reduced NHEJ activity, and increased Ku70 acetylation. Furthermore, SIRT1 knockdown resulted in cell cycle arrest, induction of apoptosis and reduction of K562 cell proliferation accompanied by enhanced p53 and FOXO1 acetylation in K562 cells after etoposide treatment. Importantly, SIRT1 downregulation reduced the tumorigenesis ability of K562 cells in mouse xenografts following chemotherapy treatment. These results revealed that SIRT1 promotes the NHEJ repair pathway by deacetylating Ku70 in K562 cells, suggesting that SIRT1 is a novel therapeutic target for treating myeloid leukemia.

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