A mechanism for epithelial–mesenchymal transition and anoikis resistance in breast cancer triggered by zinc channel ZIP6 and STAT3 (signal transducer and activator of transcription 3)

Hogstrand, Christer, Kille, Peter ORCID: https://orcid.org/0000-0001-6023-5221, Ackland, Margaret Leigh, Hiscox, Stephen Edward ORCID: https://orcid.org/0000-0003-0105-2702 and Taylor, Kathryn Mary ORCID: https://orcid.org/0000-0002-9576-9490 2013. A mechanism for epithelial–mesenchymal transition and anoikis resistance in breast cancer triggered by zinc channel ZIP6 and STAT3 (signal transducer and activator of transcription 3). Biochemical Journal 455 (2) , pp. 229-237. 10.1042/BJ20130483

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Pharmacy
Subjects:	Q Science > Q Science (General) Q Science > QP Physiology
Uncontrolled Keywords:	breast cancer; cell detachment; epithelial–mesenchymal transition (EMT); LIV-1; signal transducer and activator of transcription 3 (STAT3); solute carrier family 39; member 6 (SLC39A6); ZIP6
Publisher:	Portland Press
ISSN:	0264-6021
Funders:	Wellcome Trust
Date of First Compliant Deposit:	30 March 2016
Last Modified:	10 Apr 2024 07:10
URI:	https://orca.cardiff.ac.uk/id/eprint/50347

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