SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer
SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer
复制标题
SIRT1 去乙酰化并稳定 XRCC1 以促进肺癌化疗耐药
DOI：
10.1038/s41419-019-1592-3
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发表时间：
2019-05-01
影响因子：
9
通讯作者：
Wang, Xian
中科院分区：
文献类型：
--
作者：
Yousafzai, Neelum Aziz;Zhou, Qiyin;Wang, Xian
化疗耐药是肺癌临床治疗中最重要的挑战之一。SIRT 1是一种NAD依赖性蛋白脱乙酰酶，参与多种细胞过程，如DNA损伤修复和癌症进展。SIRT 1在化疗耐药的肺癌细胞中上调，SIRT 1的基因敲除或化学抑制通过增强DNA损伤和凋亡激活来逆转化疗耐药性，同时伴有XRCC 1降解。E3连接酶β-TrCP催化XRCC 1的多聚泛素化，促进其蛋白酶体依赖性降解。SIRT 1在赖氨酸K260、K298和K431处结合并脱乙酰化XRCC 1，阻止其β-TrCP依赖性泛素化。这三个赖氨酸位点的突变消除了XRCC 1与β-TrCP的相互作用，延长了XRCC 1蛋白的半衰期。在这里，我们描述了SIRT 1通过去乙酰化和稳定XRCC 1来赋予肺癌细胞化学抗性。因此，靶向SIRT 1可能是一种新的策略，以管理肺癌的化疗耐药性，并可能其他癌症。
Chemoresistance is one of the most important challenges in the clinical management of lung cancer. SIRT1 is a NAD dependent protein deacetylase and implicated in diverse cellular processes such as DNA damage repair, and cancer progression. SIRT1 is upregulated in chemoresistant lung cancer cells, genetic knockdown or chemical inhibition of SIRT1 reversed chemoresistance by enhancing DNA damage and apoptosis activation, accompanied with XRCC1 degradation. E3 ligase β-TrCP catalyzed the poly-ubiquitination of XRCC1 to promote its proteasome-dependent degradation. SIRT1 bound and deacetylated XRCC1 at lysine K260, K298 and K431, preventing it from β-TrCP-dependent ubiquitination. Mutations of these three lysine sites in XRCC1 abrogated the interaction with β-TrCP and prolonged the half-life of XRCC1 protein. Here, we describes SIRT1 confers chemoresistance to lung cancer cells by deacetylating and stabilizing XRCC1. Therefore, targeting SIRT1 might be a new strategy to manage the chemoresistance of lung cancer, and probably other cancers.