UNG2 deacetylation confers cancer cell resistance to hydrogen peroxide-induced cytotoxicity
UNG2 deacetylation confers cancer cell resistance to hydrogen peroxide-induced cytotoxicity
复制标题
UNG2 脱乙酰化赋予癌细胞对过氧化氢诱导的细胞毒性的抵抗力。
DOI：
10.1016/j.freeradbiomed.2020.06.010
复制
发表时间：
2020-11-20
影响因子：
7.4
通讯作者：
Zhu, Wei-Guo
中科院分区：
文献类型：
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作者：
Bao, Yantao;Tong, Lili;Zhu, Wei-Guo
癌症治疗药物会产生活性氧簇(ROS)，破坏癌症基因组并导致细胞死亡。然而，癌细胞可以抵抗ROS诱导的细胞毒性并存活下来。我们发现，核定位的尿嘧啶-DNA N-糖基酶亚型2(UNG2)在防止ROS诱导的DNA损伤和使癌细胞产生耐药性方面具有关键作用。在生理条件下，UNG2通过与E3连接酶uhrf1的相互作用而被快速降解。然而，作为对ROS的反应，癌细胞中的UNG2蛋白表现出显著延长的半衰期。在ROS暴露下，UNG2在赖氨酸78位被组蛋白去乙酰化酶去乙酰化，这阻止了UNG2-uhrf1的相互作用。因此，累积的UNG2蛋白可以切除被ROS破坏的碱基，使细胞能够在这些原本有毒的条件下生存下来。因此，将HDAC抑制剂(允许UNG2降解)与遗传毒性药物(产生细胞毒性水平的ROS)结合在一起，在体外可以在癌细胞中产生强大的协同杀伤效应。总之，这些数据支持一种新的癌症治疗方法的应用，该方法基于使用HDAC抑制剂改变UNG2的乙酰化状态来促进其降解。
Cancer therapeutics produce reactive oxygen species (ROS) that damage the cancer genome and lead to cell death. However, cancer cells can resist ROS-induced cytotoxicity and survive. We show that nuclear-localized uracil-DNA N-glycosylase isoform 2 (UNG2) has a critical role in preventing ROS-induced DNA damage and enabling cancer-cell resistance. Under physiological conditions, UNG2 is targeted for rapid degradation via an interaction with the E3 ligase UHRF1. In response to ROS, however, UNG2 protein in cancer cells exhibits a remarkably extended half-life. Upon ROS exposure, UNG2 is deacetylated at lysine 78 by histone deacetylases, which prevents the UNG2-UHRF1 interaction. Accumulated UNG2 protein can thus excise the base damaged by ROS and enable the cell to survive these otherwise toxic conditions. Consequently, combining HDAC inhibitors (to permit UNG2 degradation) with genotoxic agents (to produce cytotoxic cellular levels of ROS) leads to a robust synergistic killing effect in cancer cells in vitro. Altogether, these data support the application of a novel approach to cancer treatment based on promoting UNG2 degradation by altering its acetylation status using an HDAC inhibitor.