SIRT1 downregulation enhances chemosensitivity and survival of adult T-cell leukemia-lymphoma cells by reducing DNA double-strand repair
SIRT1 downregulation enhances chemosensitivity and survival of adult T-cell leukemia-lymphoma cells by reducing DNA double-strand repair
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SIRT1 下调通过减少 DNA 双链修复来增强成人 T 细胞白血病-淋巴瘤细胞的化疗敏感性和存活率。
DOI：
10.3892/or.2015.4287
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发表时间：
2015-12-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Wenjun
中科院分区：
文献类型：
--
作者：
Li, Liang;Ye, Shiguang;Zhang, Wenjun
大多数用于治疗成人T细胞白血病-淋巴瘤（ATL）的化疗药物通过诱导DNA损伤直接导致细胞死亡，DNA损伤可以通过几种DNA修复途径修复。DNA损伤修复系统的活性增强有助于ATL对化疗的抗性。靶向DNA修复途径是ATL细胞对化疗药物致敏的有前途的策略。在本研究中，通过shRNA抑制SIRT 1脱乙酰酶，通过降低非同源末端连接（NHEJ）和同源重组（HR）的活性使Jurkat细胞对依托泊苷敏感。siRNA沉默SIRT 1去乙酰化酶导致细胞凋亡和细胞周期阻滞增强，而依托泊苷治疗后Jurkat细胞集落形成减少伴随着FOXO 1乙酰化水平升高。此外，SIRT 1的抑制导致NHEJ和HR的DNA损伤修复活性降低，伴随Ku 70乙酰化增加。此外，SIRT 1下调延长了Jurkat异种移植小鼠的存活时间。这些结果表明，SIRT 1通过脱乙酰化Ku 70促进Jurkat细胞中的DNA双链修复途径，并通过脱乙酰化FOXO 1增加细胞增殖。结果表明，SIRT 1是开发ATL组合治疗的潜在靶点。
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.