Oncotarget

Research Papers:

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 and Andreas Möller

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Oncotarget. 2015; 6:862-873. https://doi.org/10.18632/oncotarget.2696

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Abstract

Anna Chen1,2, Christina S.F. Wong3, Mira C.P. Liu1, Colin M. House1, Jaclyn Sceneay3, David D. Bowtell1,2,4,5, Erik W. Thompson6,7,8, Andreas Möller3

1Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Australia

2Department of Pathology, The University of Melbourne, Parkville 3010, Australia

3Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia

4Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville 3010, Australia

5Department of Biochemistry, The University of Melbourne, Parkville 3010, Australia

6The University of Melbourne Department of Surgery, St Vincent’s Hospital, Fitzroy 3065, Australia

7St Vincent’s Institute of Medical Research, Fitzroy 3065, Australia

8Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove 4000, Australia

Correspondence to:

Andreas Möller, e-mail: andreas.moller@qimr.edu.au

Received: August 06, 2014     Accepted: November 04, 2014     Published: November 18, 2014

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.


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