title: Epigenetic Activation of TWIST1 by MTDH Promotes Cancer Stem-like Cell Traits in Breast Cancer.
abstract: Cancer stem-like cells (CSC) are a cell subpopulation that can reinitiate tumors, resist chemotherapy, and give rise to metastases. Metadherin (MTDH) contributes widely to tumor growth, drug resistance, relapse, and metastasis, but its molecular mechanisms of action are not well understood. Here, we report that MTDH drives CSC expansion by promoting the expression of TWIST1, a transcription factor critical for cancer cell stemness and metastasis. MTDH activates TWIST1 expression indirectly by facilitating histone H3 acetylation on the TWIST1 promoter, a process mediated by the histone acetyltransferase CBP. Mechanistic investigations showed that MTDH interacts with CBP and prevents its ubiquitin-mediated degradation, licensing its transcriptional activation of TWIST1. In clinical specimens of breast cancer, MTDH expression correlates positively with TWIST1 expression and CSC abundance. Overall, our work revealed that MTDH promotes CSC accumulation and breast tumorigenicity by regulating TWIST1, deepening the understanding of MTDH function in cancer.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China. China Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jiatao
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Mu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China. China Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiangyin
authors.initials: X
authors.lastname: Kong
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Dengli
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, China.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China. China Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ghhu@sibs.ac.cn.
authors.forename: Guohong
authors.initials: G
authors.lastname: Hu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D016601:RNA-Binding Proteins; D015533:Transcriptional Activation / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1