2. Academic Validation
  3. MTSS1 suppresses mammary tumor-initiating cells by enhancing RBCK1-mediated p65 ubiquitination

MTSS1 suppresses mammary tumor-initiating cells by enhancing RBCK1-mediated p65 ubiquitination

  • Nat Cancer. 2020 Feb;1(2):222-234. doi: 10.1038/s43018-019-0021-y.
Min Cong 1,  Yuan Wang 1,  Yang Yang 2,  Cheng Lian 1,  Xueqian Zhuang 1,  Xiaoxun Li 1,  Peiyuan Zhang 1,  Yingjie Liu 1,  Jun Tang 3,  Qifeng Yang 4,  Xue Zhang 1,  Hua Xiong 5,  Ronggui Hu 6,  Guohong Hu 7
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Shanghai, China.
  • 3 State Key Laboratory of Oncology in South China; Department of Breast Oncology, Sun Yat-Sen University, Guangzhou, China.
  • 4 Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, China.
  • 5 Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China. cnhxiong@163.com.
  • 6 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Shanghai, China. coryhu@sibcb.ac.cn.
  • 7 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. ghhu@sibs.ac.cn.
PMID: 35122005 DOI: 10.1038/s43018-019-0021-y
Abstract

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.

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