E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation
E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation
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DOI：
10.1128/mcb.00257-19
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发表时间：
2020-04-01
影响因子：
5.3
通讯作者：
Lin, Zhenghong
中科院分区：
文献类型：
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作者：
Liu, Liu;Yu, Le;Lin, Zhenghong
NAD依赖性组蛋白去乙酰化酶sirtuin 2（SIRT 2）在有丝分裂和细胞周期进程中起着关键作用，最近被证明可以抑制肿瘤生长，并在几种类型的癌症中下调。然而，SIRT 2下调的潜在机制仍然未知。在这项研究中，使用生物信息学，基因表达谱，蛋白过表达的方法，和细胞迁移试验，我们表明，E3泛素连接酶3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶降解1（HRD 1）与SIRT 2相互作用，并促进其泛素化和降解。此外，我们发现HRD 1缺陷诱导SIRT 2上调，并在体外和体内抑制肺癌细胞的生长和肿瘤形成。值得注意的是，我们观察到SIRT 2表达在人肺癌中下调，并且与这些癌症中的HRD 1表达呈负相关。此外，我们发现具有较低HRD 1或较高SIRT 2表达水平的肺腺癌患者倾向于存活更长时间。在这些结果的基础上，我们提出了一种涉及HRD 1介导的SIRT 2下调的肺肿瘤发生机制，并建议针对HRD 1活性的干预措施可能是治疗肺癌患者的潜在治疗策略。
The NAD-dependent histone deacetylase sirtuin 2 (SIRT2) plays critical roles in mitosis and cell cycle progression and recently was shown to suppress tumor growth and to be downregulated in several types of cancers. However, the underlying mechanism of SIRT2 downregulation remains unknown. In this study, using bioinformatics, gene expression profiling, protein overexpression approaches, and cell migration assays, we showed that E3 ubiquitin ligase 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase degradation 1 (HRD1) interacts with SIRT2 and promotes its ubiquitination and degradation. Furthermore, we found that HRD1 deficiency induces SIRT2 upregulation and inhibits the growth and tumor formation of lung cancer cells both in vitro and in vivo. Of note, we observed that SIRT2 expression is downregulated in human lung cancer and also negatively correlates with HRD1 expression in these cancers. Additionally, we found that patients with lung adenocarcinoma having lower HRD1 or higher SIRT2 expression levels tend to survive longer. On the basis of these results, we propose a mechanism of lung tumorigenesis that involves HRD1-mediated downregulation of SIRT2 and suggest that interventions targeting HRD1 activity could be a potential therapeutic strategy to treat patients with lung cancer.