SIRT2 inhibits non-small cell lung cancer cell growth through impairing Skp2-mediated p27 degradation.
SIRT2 inhibits non-small cell lung cancer cell growth through impairing Skp2-mediated p27 degradation.
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SIRT2 通过损害 Skp2 介导的 p27 降解抑制非小细胞肺癌细胞生长
DOI：
10.18632/oncotarget.7816
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发表时间：
2016-04-05
期刊：
影响因子：
--
通讯作者：
Lu S
中科院分区：
文献类型：
--
作者：
Li Z;Huang J;Yuan H;Chen Z;Luo Q;Lu S
Skp2是E3泛素连接酶的一个组成部分，它促进细胞周期蛋白依赖的激酶抑制物p27的泛素化相关降解，导致非小细胞肺癌(NSCLC)细胞生长增加。我们最近发现，在非小细胞肺癌中，Sirtuin脱乙酰酶2(SIRT2)的下调通过抑制p27来促进癌细胞的生长。然而，潜在的机制仍不清楚。在这里，我们研究了SIRT2和Skp2在通过p27调节NSCLC细胞生长中的关系。我们发现，与配对的非肿瘤肺组织相比，非小细胞肺癌组织中SIRT2的水平显著降低，而Skp2的水平显著上升。SIRT2和Skp2水平呈负相关。低SIRT2水平与不良患者的生存相关。此外，在几种肺癌细胞系中，SIRT2水平显著降低，Skp2水平显著升高。SIRT2过表达促进Skp2去乙酰化和降解，导致p27增加，抑制NSCLC细胞生长；而Skp2基因敲除抑制Skp2去乙酰化和降解，导致p27减少，NSCLC细胞生长增加。组蛋白脱乙酰酶抑制剂和蛋白酶体抑制剂分别显著抑制SIRT2对Skp2的脱乙酰化和Skp2对p27的降解。最后，SIRT2和Skp2在NSCLC细胞内免疫共沉淀。综上所述，我们的数据表明，SIRT2可能诱导Skp2去乙酰化和随后的降解，以消除Skp2对p27的影响，从而影响NSCLC细胞的生长。因此，SIRT2的重新表达可能成为治疗非小细胞肺癌的一种有前途的策略。
Skp2 is a component of the E3 ubiquitin ligase which promotes the ubiquitination-associated degradation of a cyclin-dependent kinase inhibitor, p27, resulting in increases in non-small cell lung cancer (NSCLC) cell growth. We recently showed that down-regulation of Sirtuin deacetylases 2 (SIRT2) in NSCLC increased cancer cell growth through suppressing p27. However, the underlying mechanisms remain unknown. Here, we examined the relationship between SIRT2 and Skp2 in regulation of NSCLC cell growth through p27. We found that the levels of SIRT2 significantly decreased, while the levels of Skp2 significantly increased in NSCLC specimens, compared to the paired non-tumor lung tissue. The levels of SIRT2 and Skp2 inversely correlated. Low SIRT2 levels were associated with poor patients' survival. Moreover, in several lung cancer cell lines, the SIRT2 levels significantly decreased and the Skp2 levels significantly increased. Overexpression of SIRT2 promoted Skp2 deacetylation and degradation, resulting in increases in p27 and suppression of NSCLC cell growth, whereas knockdown of Skp2 inhibited Skp2 deacetylation and degradation, resulting in decreases in p27 and increases in NSCLC cell growth. The deacetylation of Skp2 by SIRT2 and degradation of p27 by Skp2 were significantly inhibited by histone deacetylase inhibitor and proteasome inhibitor, respectively. Finally, SIRT2 and Skp2 co-immunoprecipitated in NSCLC cells. Together, our data suggest that SIRT2 may induce Skp2 deacetylation and subsequent degradation to abolish the effects of Skp2 on p27 to affect NSCLC cell growth. Thus, re-expression of SIRT2 may be a promising strategy for treating NSCLC.