KCNN1, an integral membrane protein, is thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. However, the role of KCNN1 in tumorigenesis has been rarely reported, and the underlying molecular mechanism remains unclear. Here, we report that KCNN1 functions as an oncogene in promoting breast cancer cell proliferation and metastasis. KCNN1 was overexpressed in breast cancer tissues and cells. The pro-proliferative and pro-metastatic effects of KCNN1 were demonstrated by CCK8, clone formation, Edu assay, wound healing assay and transwell experiments. Transcriptomic analysis using KCNN1 overexpressing cells revealed that KCNN1 could regulate key signaling pathways affecting the survival of breast cancer cells. KCNN1 interacts with ERLIN2 and enhances the effect of ERLIN2 on Cyclin B1 stability. Overexpression of KCNN1 promoted the protein expression of Cyclin B1, enhanced its stability and promoted its K63 dependent ubiquitination, while knockdown of KCNN1 had the opposite effects on Cyclin B1. Knockdown (or overexpression) ERLNI2 partially restored Cyclin B1 stability and K63 dependent ubiquitination induced by overexpression (or knockdown) of KCNN1. Knockdown (or overexpression) ERLIN2 also partially neutralizes the effects of overexpression (or knockdown) KCNN1-induced breast cancer cell proliferation, migration, and invasion. In paired breast cancer clinical samples, we found a positive expression correlations between KCNN1 and ERLIN2, KCNN1 and Cyclin B1, as well as ERLIN2 and Cyclin B1. In conclusion, this study reveals, for the first time, the role of KCNN1 in tumorigenesis and emphasizes the importance of KCNN1/ERLIN2/Cyclin B1 axis in the development and metastasis of breast cancer.

中文翻译：

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KCNN1 通过 ERLIN2 介导的稳定和 K63 依赖的 Cyclin B1 泛素化促进乳腺癌的增殖和转移。

KCNN1 是一种完整的膜蛋白，被认为通过促进突触后超极化的缓慢成分来调节神经元兴奋性。然而，KCNN1在肿瘤发生中的作用鲜有报道，其潜在的分子机制仍不清楚。在此，我们报道 KCNN1 作为癌基因促进乳腺癌细胞增殖和转移。KCNN1 在乳腺癌组织和细胞中过度表达。KCNN1 的促增殖和促转移作用通过 CCK8、克隆形成、Edu 测定、伤口愈合测定和 Transwell 实验得到证明。使用 KCNN1 过表达细胞的转录组分析表明，KCNN1 可以调节影响乳腺癌细胞存活的关键信号通路。KCNN1 与 ERLIN2 相互作用，增强 ERLIN2 对 Cyclin B1 稳定性的影响。KCNN1的过表达促进了Cyclin B1蛋白的表达，增强了其稳定性并促进了其K63依赖性泛素化，而KCNN1的敲除对Cyclin B1有相反的影响。敲低（或过表达）ERLNI2 部分恢复了由 KCNN1 过表达（或敲低）诱导的 Cyclin B1 稳定性和 K63 依赖性泛素化。敲低（或过度表达）ERLIN2 还可部分中和过度表达（或敲低）KCNN1 诱导的乳腺癌细胞增殖、迁移和侵袭的影响。在配对的乳腺癌临床样本中，我们发现 KCNN1 和 ERLIN2、KCNN1 和 Cyclin B1、以及 ERLIN2 和 Cyclin B1 之间存在正表达相关性。总之，本研究首次揭示了KCNN1在肿瘤发生中的作用，并强调了KCNN1/ERLIN2/Cyclin B1轴在乳腺癌发生和转移中的重要性。