MTSS1 suppresses mammary tumor-initiating cells by enhancing RBCK1-mediated p65 ubiquitination.
Min CongYuan WangYang YangCheng LianXueqian ZhuangXiaoxun LiPeiyuan ZhangYingjie LiuJun TangQifeng YangXue ZhangHua XiongRonggui HuGuo-Hong HuPublished in: Nature cancer (2020)
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. Mtss1 knockout (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, MTSS1 silencing 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.
Keyphrases
- signaling pathway
- induced apoptosis
- pi k akt
- cell cycle arrest
- epithelial mesenchymal transition
- papillary thyroid
- breast cancer cells
- oxidative stress
- cell proliferation
- electronic health record
- genome wide
- cell death
- nuclear factor
- endoplasmic reticulum stress
- immune response
- inflammatory response
- big data
- dna binding