RNF8 Promotes Epithelial-Mesenchymal Transition in Lung Cancer Cells via Stabilization of Slug
RNF8 Promotes Epithelial-Mesenchymal Transition in Lung Cancer Cells via Stabilization of Slug
复制标题
RNF8 通过稳定 Slug 促进肺癌细胞的上皮-间质转化
DOI：
10.1158/1541-7786.mcr-19-1211
复制
发表时间：
2020-11-01
影响因子：
5.2
通讯作者：
Zhu, Lingyun
中科院分区：
文献类型：
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作者：
Kuang, Jingyu;Min, Lu;Zhu, Lingyun
RNF 8（ring finger protein 8）是一种环指蛋白E3连接酶，其特征在于通过泛素化在DNA修复和精子形成中发挥作用，最近被发现促进乳腺癌的肿瘤转移。然而，RNF 8是否也在其他类型的癌症中发挥作用，特别是在肺癌中，仍然未知。我们发现RNF 8的表达水平在人肺癌组织中显著增加，并与患者的生存时间呈负相关。RNF 8的过表达促进了肺癌细胞的EMT过程和迁移能力，而RNF 8的敲低则表现出相反的效果。此外，RNF 8的过表达激活了PI 3 K/Akt信号通路，通过siRNA敲低RNF 8抑制了这种激活，并且在RNF 8过表达细胞中对PI 3 K/ Akt的药理学抑制也降低了EMT标志物的表达和迁移能力。此外，RNF 8被发现直接与Slug相互作用并促进Slug的K63-Ub，并且Slug的敲低破坏了A549细胞中RNF 8依赖的EMT，而Slug的过表达挽救了H1299细胞中RNF 8依赖的MET，并且通过shRNA耗尽RNF 8表达抑制了肺癌细胞的体内转移。总之，这些结果表明RNF 8是肺癌EMT过程的关键调节因子，并表明抑制RNF 8可能是肺癌治疗的有用策略。
RNF8 (ring finger protein 8), a RING finger E3 ligase best characterized for its role in DNA repair and sperm formation via ubiquitination, has been found to promote tumor metastasis in breast cancer recently. However, whether RNF8 also plays a role in other types of cancer, especially in lung cancer, remains unknown. We show here that RNF8 expression levels are markedly increased in human lung cancer tissues and negatively correlated with the survival time of patients. Overexpression of RNF8 promotes the EMT process and migration ability of lung cancer cells, while knockdown of RNF8 demonstrates the opposite effects. In addition, overexpression of RNF8 activates the PI3K/Akt signaling pathway, knockdown of RNF8 by siRNA inhibits this activation, and pharmacologic inhibition of PI3K/ Akt in RNF8-overexpressing cells also reduces the expression of EMT markers and the ability of migration. Furthermore, RNF8 is found to directly interact with Slug and promoted the K63-Ub of Slug, and knockdown of Slug disrupts RNF8-dependent EMT in A549 cells, whereas overexpression of Slug rescues RNF8-dependent MET in H1299 cells, and depletion of RNF8 expression by shRNA inhibits metastasis of lung cancer cells in vivo. Taken together, these results indicate that RNF8 is a key regulator of EMT process in lung cancer and suggest that inhibition of RNF8 could be a useful strategy for lung cancer treatment.