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

Anna Chen; Christina S F Wong; Mira C P Liu; Colin M House; Jaclyn Sceneay; David D Bowtell; Erik W Thompson; Andreas Möller

doi:10.18632/oncotarget.2696

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

Oncotarget. 2015 Jan 20;6(2):862-73. doi: 10.18632/oncotarget.2696.

Authors

Anna Chen^{1

2}, Christina S F Wong³, Mira C P Liu¹, Colin M House¹, Jaclyn Sceneay³, David D Bowtell^{1

2

4

5}, Erik W Thompson^{6

7

8}, Andreas Möller³

Affiliations

¹ Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia.
² Department of Pathology, The University of Melbourne, Parkville 3010, Australia.
³ Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
⁴ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville 3010, Australia.
⁵ Department of Biochemistry, The University of Melbourne, Parkville 3010, Australia.
⁶ The University of Melbourne Department of Surgery, St Vincent's Hospital, Fitzroy 3065, Australia.
⁷ St Vincent's Institute of Medical Research, Fitzroy 3065, Australia.
⁸ Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove 4000, Australia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line
Cell Line, Tumor
Epithelial-Mesenchymal Transition / drug effects
Epithelial-Mesenchymal Transition / genetics*
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Homeodomain Proteins / genetics*
Homeodomain Proteins / metabolism
Humans
MCF-7 Cells
Mice
Microscopy, Fluorescence
Models, Genetic
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects
Signal Transduction / genetics
Transcription Factors / genetics*
Transcription Factors / metabolism
Transforming Growth Factor alpha / pharmacology
Transforming Growth Factor beta / pharmacology
Ubiquitin-Protein Ligases / genetics*
Ubiquitin-Protein Ligases / metabolism
Zinc Finger E-box-Binding Homeobox 1

Substances

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