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PMID: 25528765 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer.

Oncotarget ·Vol. 6 ·No. 2 ·2015-01-20 ·Pages 862-73

Chen A, Wong CS, Liu MC, House CM, Sceneay J, Bowtell DD, Thompson EW, Möller A

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.

MeSH Terms
Animals Blotting, Western Breast Neoplasms/genetics,metabolism,pathology Cell Line Cell Line, Tumor Epithelial-Mesenchymal Transition/drug effects,genetics Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Homeodomain Proteins/genetics,metabolism Humans MCF-7 Cells Mice Microscopy, Fluorescence Models, Genetic Nuclear Proteins/genetics,metabolism RNA Interference Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/drug effects,genetics Transcription Factors/genetics,metabolism Transforming Growth Factor alpha/pharmacology Transforming Growth Factor beta/pharmacology Ubiquitin-Protein Ligases/genetics,metabolism Zinc Finger E-box-Binding Homeobox 1
Chemicals
Homeodomain Proteins Nuclear Proteins Transcription Factors Transforming Growth Factor alpha Transforming Growth Factor beta ZEB1 protein, human Zinc Finger E-box-Binding Homeobox 1 Ubiquitin-Protein Ligases seven in absentia proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Chen Anna
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.
Wong Christina S F
Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
Liu Mira C P
Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia.
House Colin M
Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia.
Sceneay Jaclyn
Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
Bowtell David D
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.
Thompson Erik W
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.
Möller Andreas
Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
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Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.2696
Published
2015-01-20
Pages
862-73
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4359261
Subset
IM
External Links
PubMed source DOI: 10.18632/oncotarget.2696 PMC Full Text View journal details
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