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

// Anna Chen 1, 2 , Christina S.F. Wong 3 , Mira C.P. Liu 1 , Colin M. House 1 , Jaclyn Sceneay 3 , David D. Bowtell 1, 2, 4, 5 , Erik W. Thompson 6, 7, 8 , Andreas Möller 3 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 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.