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: Liang Li, Shiguang Ye, Meng Yang, Wenlei Yu, Zhuoyi Fan, Hong Zhang, Jiong Hu, Aibin Liang, Wenjun Zhang
• Journal: Oncology reports (Oncol Rep) Vol. 34 Issue 6 Pg. 2935-42 (Dec 2015) ISSN: 1791-2431 [Electronic] Greece
• PMID: 26398583 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Nuclear
• DNA-Binding Proteins
• FOXO1 protein, human
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Etoposide
• SIRT1 protein, human
• Sirtuin 1
• Xrcc6 protein, human
• Xrcc6 protein, mouse
• Ku Autoantigen

Topics

• Adult
• Animals
• Antigens, Nuclear (genetics)
• DNA Breaks, Double-Stranded (drug effects)
• DNA Damage (genetics)
• DNA End-Joining Repair (genetics)
• DNA Repair (genetics)
• DNA-Binding Proteins (genetics)
• Drug Resistance, Neoplasm (genetics)
• Etoposide (administration & dosage)
• Forkhead Box Protein O1
• Forkhead Transcription Factors (genetics)
• Homologous Recombination (genetics)
• Humans
• Jurkat Cells
• Ku Autoantigen
• Leukemia-Lymphoma, Adult T-Cell (drug therapy, genetics, pathology)
• Mice
• Sirtuin 1 (antagonists & inhibitors, biosynthesis, genetics)
• Xenograft Model Antitumor Assays