Publications

Publication: A Mechanism for Epithelial-Mesenchymal Transition and Anoikis Resistance in Breast Cancer Triggered by Zinc Channel ZIP6 and Signal Transducer and Activator of Transcription 3 (STAT3)

Professor Kille is part of a collaboration in Cardiff that has published their latest findings on the mechanism involved with zinc channels in breast cancer.

The advance publication is available here

A Mechanism for Epithelial-Mesenchymal Transition and Anoikis Resistance in Breast Cancer Triggered by Zinc Channel ZIP6 and Signal Transducer and Activator of Transcription 3 (STAT3)

Christer Hogstrand, Peter Kille, Margaret Leigh Ackland, Stephen Hiscox and Kathryn M Taylor. Cardiff University, CARDIFF, United Kingdom.

Genes involved in normal developmental processes attract attention as mediators of tumour progression as they facilitate migration of tumour cells. Epithelial-mesenchymal transition (EMT), an essential part of embryonic development, tissue remodelling and wound repair, is crucial for tumour metastasis. Previously zinc transporter ZIP6 (SLC39A6, LIV-1) was linked to EMT in zebrafish gastrulation through a STAT3 mechanism resulting in nuclear localisation of transcription factor Snail. Here we show that zinc transporter ZIP6 is transcriptionally induced by STAT3 and unprecedented among zinc transporters is activated by N-terminal cleavage which triggers ZIP6 plasma membrane location and zinc influx. This zinc influx inactivates GSK-3β, either indirectly or directly via AKT or GSK-3β, respectively, resulting in activation of Snail, which remains in the nucleus and acts as a transcriptional repressor of E-cadherin, CDH1, causing cell rounding and detachment. This was mirrored by ZIP6-transfected cells which underwent EMT, detached from monolayers and exhibited resistance to anoikis by their ability to continue proliferating even after detachment. Our results indicate a causative role for ZIP6 in cell motility and migration, providing ZIP6 as a new target for prediction of clinical cancer spread and also suggesting a ZIP6-dependant mechanism of tumour metastasis.


doi:10.1042/BJ20130483
Received 5 April 2013/15 July 2013; Accepted 7 August 2013
Published as Immediate Publication 7 August 2013