title: CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression.
abstract: The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.
authors.affiliation: Authors' Affiliations: Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine; Department of Respiratory Medicine, Qilu Hospital, Shandong University, Jinan; International Biotechnology R&D Center, Shandong University School of Ocean, Weihai, Shandong, China; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley; Department of Pathology; Thoracic Oncology Laboratory, Department of Surgery; Helen Diller Family Comprehensive Cancer Center and Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California; and Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon.
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Wang
authors.forename: Mingxin
authors.initials: M
authors.lastname: Wen
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Kwon
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Xu
authors.forename: Yueyong
authors.initials: Y
authors.lastname: Liu
authors.forename: Pengju
authors.initials: P
authors.lastname: Zhang
authors.forename: Xiuquan
authors.initials: X
authors.lastname: He
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Yurong
authors.initials: Y
authors.lastname: Huang
authors.forename: Kuang-Yu
authors.initials: KY
authors.lastname: Jen
authors.forename: Mark A
authors.initials: MA
authors.lastname: LaBarge
authors.forename: Liang
authors.initials: L
authors.lastname: You
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Guangwei
authors.initials: G
authors.lastname: Wei
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C114234:CUL4A protein, human; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D006657:Histones; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1