title: SIRT1 downregulation enhances chemosensitivity and survival of adult T-cell leukemia-lymphoma cells by reducing DNA double-strand repair.
abstract: Most chemotherapy drugs used for the treatment of adult T-cell leukemia-lymphoma (ATL) cause cell death directly by inducing DNA damage, which can be repaired via several DNA repair pathways. Enhanced activity of DNA damage repair systems contributes to ATL resistance to chemotherapies. Targeting DNA repair pathways is a promising strategy for the sensitization of ATL cells to chemotherapeutic drugs. in the present study, inhibition of SIRT1 deacetylase by shRNA sensitized Jurkat cells to etoposide by reducing the activity of non-homologous end joining (NHEJ) and homologous recombination (HR). Silencing of SIRT1 deacetylase by shRNA resulted in enhanced apoptosis and cell cycle arrest, while reduced colony formation of Jurkat cells after etoposide treatment was accompanied by elevated acetylation of FOXO1. Furthermore, inhibition of SIRT1 led to decreased activity of DNA damage repair by NHEJ and HR, accompanied by increased Ku70 acetylation. Furthermore, SIRT1 downregulation prolonged the survival time of Jurkat-xenografted mice. These results suggested that SIRT1 promotes DNA double‑strand repair pathways in Jurkat cells by deacetylating Ku70, and increases cell proliferation by deacetylating FOXO1. The results suggest that SIRT1 is a potential target for the development of combinatorial treatment for ATL.
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Ye
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Wenlei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Zhuoyi
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Clinical Pharmacology Department, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Aibin
authors.initials: A
authors.lastname: Liang
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000235:genetics; D059766:DNA End-Joining Repair / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000008:administration & dosage; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D000072200:Ku Autoantigen; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005047:Etoposide; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen