title: The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer.
abstract: Elucidating the mechanisms that underlie metastasis is of paramount importance to understanding tumor progression and to the development of novel therapeutics. Epithelial to Mesenchymal Transition (EMT) plays a vital role in tumor cell dissemination and is regulated by a core cassette of transcription factors. Despite recent advances, the molecular pathways that regulate the EMT program have not yet been fully delineated. We show that Siah ubiquitin ligases regulate Zeb1 protein, a key EMT transcription factor. The induction of EMT in breast cancer cells leads to the down-regulation of Siah, while the loss of Siah induces a mesenchymal phenotype, concurrent with an up-regulation of Zeb1. Overexpression of Siah in vitro mediates Zeb1 degradation, which can be blocked with a Siah peptide inhibitor. Thus, this work demonstrates that Siah is a novel regulator of EMT. This work is the first to identify a mechanism of post-translational regulation of the key Epithelial to Mesenchymal Transition transcription factor Zeb1.
authors.affiliation: Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia.|Department of Pathology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Chen
authors.affiliation: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
authors.forename: Christina S F
authors.initials: CS
authors.lastname: Wong
authors.affiliation: Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia.
authors.forename: Mira C P
authors.initials: MC
authors.lastname: Liu
authors.affiliation: Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia.
authors.forename: Colin M
authors.initials: CM
authors.lastname: House
authors.affiliation: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Sceneay
authors.affiliation: Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia.|Department of Pathology, The University of Melbourne, Parkville 3010, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville 3010, Australia.|Department of Biochemistry, The University of Melbourne, Parkville 3010, Australia.
authors.forename: David D
authors.initials: DD
authors.lastname: Bowtell
authors.affiliation: The University of Melbourne Department of Surgery, St Vincent's Hospital, Fitzroy 3065, Australia.|St Vincent's Institute of Medical Research, Fitzroy 3065, Australia.|Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove 4000, Australia.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
authors.affiliation: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000098563:Seven in Absentia Proteins
chemical_list: D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins