Stabilization of P/CAF, as a ubiquitin ligase toward MDM2, suppresses mitotic cell death through p53-p21 activation in HCT116 cells with SIRT2 suppression.
Stabilization of P/CAF, as a ubiquitin ligase toward MDM2, suppresses mitotic cell death through p53-p21 activation in HCT116 cells with SIRT2 suppression.
复制标题
P/CAF 作为一种针对 MDM2 的泛素连接酶，可通过 HCT116 细胞中 p53-p21 的激活以及 SIRT2 抑制来抑制有丝分裂细胞死亡。
DOI：
10.1016/j.bbrc.2018.11.136
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Inoue T.
中科院分区：
文献类型：
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作者：
Li Y;Kokura K;Inoue T.
我们此前曾报道，抑制NAD+依赖性蛋白去乙酰基酶SIRT2，通过降解p300和随后的MDM2降解，诱导P53积聚，最终导致HeLa细胞凋亡。本研究发现了一种通过抑制SIRT2在HCT116细胞(P53+/+)中积聚P53的新途径，该途径通过抑制SIRT2而使有丝分裂细胞逃脱诺考达唑等微管抑制剂诱导的纺锤体组装检查点激活引起的有丝分裂细胞死亡，而不是导致细胞凋亡或G1期或G2期停滞。我们发现SIRT2与组蛋白乙酰转移酶P/CAF相互作用，组蛋白乙酰转移酶也是MDM2的泛素连接酶。抑制SIRT2后，P/CAF乙酰化水平增加并趋于稳定，MDM2水平降低，p53-p21通路激活。抑制P/CAF或p21可抑制SIRT2抑制的HCT116(P53+/+)细胞有丝分裂细胞死亡。因此，P/Caf-MDM2-P53-p21轴使有丝分裂细胞能够逃脱死亡，并在抑制SIRT2的HCT116(P53+/+)细胞中对诺可唑产生耐药性。由于SIRT2作为P53调控肿瘤治疗的潜在靶点而备受关注，本研究为SIRT2在未来基于P53调控的肿瘤治疗中的有效性提供了分子基础。这些发现还表明，与激活P53-p21通路相关的SIRT2抑制在抑制纺锤体组件检查点激活引起的有丝分裂细胞死亡方面具有不良功能。
We previously reported that the suppression of SIRT2, an NAD + -dependent protein deacetylases, induces p53 accumulation via degradation of p300 and the subsequent MDM2 degradation, eventually leading to apoptosis in HeLa cells. The present study identified a novel pathway of p53 accumulation by SIRT2 suppression in HCT116(p53+/+) cells in which SIRT2 suppression led to escape from mitotic cell death caused by spindle assembly checkpoint activation induced by microtubule inhibitors such as nocodazole but not apoptosis or G1 or G2 arrest. We found that SIRT2 interacts with P/CAF, a histone acetyltransferase, which also acts as a ubiquitin ligase against MDM2. SIRT2 suppression led to an increase of P/CAF acetylation and its stabilization followed by a decrease in MDM2 and activation of the p53-p21 pathway. Depression of mitotic cell death in HCT116(p53+/+) cells with SIRT2 suppression was released by suppression of P/CAF or p21. Thus, the P/CAF-MDM2-p53-p21 axis enables the escape from mitotic cell death and confers resistance to nocodazole in HCT116(p53+/+) cells with SIRT2 suppression. As SIRT2 has attracted attention as a potential target for cancer therapeutics for p53 regulation, the present study provides a molecular basis for the efficacy of SIRT2 for future cancer therapy based on p53 regulation. These findings also suggest an undesirable function of the SIRT2 suppression associated with activation of the p53-p21 pathway in the suppression of mitotic cell death caused by spindle assembly checkpoint activation.