MTSS1 suppresses mammary tumor-initiating cells by enhancing RBCK1-mediated p65 ubiquitination
MTSS1 suppresses mammary tumor-initiating cells by enhancing RBCK1-mediated p65 ubiquitination
复制标题
MTSS1 通过增强 RBCK1 介导的 p65 泛素化来抑制乳腺肿瘤起始细胞
DOI：
10.1038/s43018-019-0021-y
复制
发表时间：
2020-02-01
期刊：
影响因子：
22.7
通讯作者：
Hu, Guohong
中科院分区：
文献类型：
--
作者：
Cong, Min;Wang, Yuan;Hu, Guohong
肿瘤起始细胞（TIC）被认为是癌症发展和进展的罪魁祸首。转移抑制蛋白1（MTSS 1）的失调在肿瘤转移中被广泛观察到，但其在癌症中的功能贡献和机制知之甚少。在此，我们报道了MTSS 1在乳腺癌中抑制TIC的作用。Mtss 1敲除（KO）增强了管腔型和基底型乳腺癌小鼠模型中乳腺上皮TIC亚群。MTSS 1还抑制乳腺癌细胞中的肿瘤球形成。MTSS 1与E3连接酶RanBP 2型和C3 HC 4型锌指蛋白1（RBCK 1）相互作用，促进RBCK 1介导的p65泛素化和降解，从而抑制NF-κB信号通路和肿瘤发生。此外，肌动蛋白β样2（ACTBL 2）与RBCK 1竞争MTSS 1结合，导致p65稳定。重要的是，MTSS 1沉默促进患者源性类器官形成和异种移植物生长。临床肿瘤中MTSS 1的下调也与更差的预后有关。总的来说，我们的数据揭示了NF-κB调控的新模式，并可能在靶向TIC的治疗中具有重要意义。
Tumor-initiating cells (TICs) are considered the culprits of cancer development and progression. Dysregulation of metastasis suppressor protein 1 (MTSS1) has been widely observed in tumor metastasis, but its functional contribution and mechanism in cancer is poorly understood. Here we report a role of MTSS1 in suppressing TICs in breast cancer.Mtss1knockout (KO) enhances the mammary epithelial TIC subpopulation in both luminal and basal-like breast cancer mouse models. MTSS1 also suppresses tumorsphere formation in breast cancer cells. Mechanistically, MTSS1 interacts with the E3 ligase RanBP2-type and C3HC4-type zinc finger containing 1 (RBCK1) to facilitate RBCK1-mediated p65 ubiquitination and degradation, thus suppressing the NF-κB signaling pathway and tumorigenesis. In addition, actin beta-like 2 (ACTBL2) competes with RBCK1 for MTSS1 binding, leading to p65 stabilization. Importantly,MTSS1silencing promotes patient-derived organoid formation and xenograft growth. MTSS1 downregulation in clinical tumors is also linked to worse prognosis. Overall our data reveal a new paradigm of NF-κB regulation and may have important implications in therapeutics targeting TICs.