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. Implications: This study provides a new mechanistic insight into the novel role of RNF8 and identifies RNF8 as a potential new therapeutic target for the treatment of lung cancer.

中文翻译：

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RNF8通过稳定Slug促进肺癌细胞上皮间质转化

RNF8（无名指蛋白 8）是一种无名指 E3 连接酶，其特征是通过泛素化在 DNA 修复和精子形成中发挥作用，最近已发现它可促进乳腺癌的肿瘤转移。然而，RNF8 是否也在其他类型的癌症中发挥作用，尤其是在肺癌中，仍然未知。我们在这里表明，RNF8 表达水平在人肺癌组织中显着增加，并且与患者的生存时间呈负相关。RNF8的过表达促进了肺癌细胞的EMT过程和迁移能力，而RNF8的敲低则表现出相反的效果。此外，RNF8 的过表达激活了 PI3K/Akt 信号通路，siRNA 对 RNF8 的敲低抑制了这种激活，在 RNF8 过表达细胞中对 PI3K/Akt 的药理抑制也会降低 EMT 标志物的表达和迁移能力。此外，发现 RNF8 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 细胞中依赖于 RNF8 的 EMT，而 Slug 的过表达挽救了 H1299 细胞中依赖于 RNF8 的 MET，并耗尽了 RNF8 的表达通过 shRNA 在体内抑制肺癌细胞的转移。总之，这些结果表明 RNF8 是肺癌 EMT 过程的关键调节因子，并表明抑制 RNF8 可能是肺癌治疗的有用策略。启示：本研究为 RNF8 的新作用提供了新的机制见解，并将 RNF8 确定为治疗肺癌的潜在新治疗靶点。