title: FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development.
abstract: The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA; College of Life Science, Jilin University, Changchun, 130023, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA.
authors.forename: Anitha K
authors.initials: AK
authors.lastname: Shenoy
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Doernberg
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA.
authors.forename: Huacheng
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Florida College of Medicine Gainesville, FL 32610, USA.
authors.forename: Huangxuan
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Tarrash
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Cai
authors.affiliation: College of Life Science, Jilin University, Changchun, 130023, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Animal Care Services, NF/SG VHS Malcom Randal VA Medical Center, Gainesville, FL 32610, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Fiske
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Florida College of Medicine Gainesville, FL 32610, USA.
authors.forename: Lizi
authors.initials: L
authors.lastname: Wu
authors.affiliation: Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, University of Florida College of Medicine, NF/SG VHS Malcom Randal VA Medical Center, Gainesville, FL 32610, USA.
authors.forename: Kamal A
authors.initials: KA
authors.lastname: Mohammed
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Veerle
authors.initials: V
authors.lastname: Rottiers
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Siu Sylvia
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA. Electronic address: jrlu@ufl.edu.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D017173:Caenorhabditis elegans; D018450:Disease Progression; D004817:Epidermis / Q000254:growth & development / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C515669:Fbxo11 protein, mouse; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C457579:FBXO11 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: E-cadherin; EMT; Epidermis; F-box; Scratch; Snai1
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