Transcription factor SNAI2 plays key roles during development and has also been known to promote metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. However, the post-translational regulation of SNAI2 is less well studied. We performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation. ASB13 knockout in breast cancer cells promoted cell migration and decreased F-actin polymerization, while overexpression of ASB13 suppressed lung metastasis. Furthermore, ASB13 knockout decreased YAP expression, and such regulation is dependent on an increased protein level of SNAI2, which in turn represses YAP transcription. YAP suppresses tumor progression in breast cancer, as YAP knockout increases tumorsphere formation, anchorage-independent colony formation, cell migration in vitro, and lung metastasis in vivo. Clinical data analysis reveals that ASB13 expression is positively correlated with improved overall survival in breast cancer patients. These findings establish ASB13 as a suppressor of breast cancer metastasis by promoting degradation of SNAI2 and relieving its transcriptional repression of YAP.

中文翻译：

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ASB13 通过促进 SNAI2 降解和减轻其对 YAP 的转录抑制来抑制乳腺癌转移。

转录因子 SNAI2 在发育过程中起着关键作用，并且还已知通过诱导癌细胞的侵袭性表型和肿瘤起始活性来促进转移。然而，SNAI2 的翻译后调控研究较少。我们进行了基于双荧光素酶的全基因组 E3 连接酶 siRNA 文库筛选，并将 ASB13 鉴定为 E3 泛素连接酶，靶向 SNAI2 进行泛素化和降解。乳腺癌细胞中的 ASB13 敲除促进细胞迁移并减少 F-肌动蛋白聚合，而 ASB13 的过表达抑制肺转移。此外，ASB13 敲除降低了 YAP 表达，并且这种调节依赖于 SNAI2 蛋白质水平的增加，这反过来又抑制了 YAP 转录。YAP 抑制乳腺癌的肿瘤进展，因为 YAP 敲除增加了肿瘤球的形成、不依赖锚定的集落形成、体外细胞迁移和体内肺转移。临床数据分析表明，ASB13 表达与乳腺癌患者总生存期的改善呈正相关。这些发现通过促进 SNAI2 的降解和减轻其对 YAP 的转录抑制，将 ASB13 确立为乳腺癌转移的抑制剂。