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)
- Authors
- Hogstrand, C., Kille, P., Ackland, M.L., Hiscox, S., and Taylor, K.M.
- ID
- ZDB-PUB-130830-4
- Date
- 2013
- Source
- The Biochemical journal 455(2): 229-37 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- CHO Cells
- Cation Transport Proteins/genetics*
- Cation Transport Proteins/metabolism
- Epithelial-Mesenchymal Transition/genetics*
- Cricetulus
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Humans
- Animals
- Cadherins/genetics
- Cadherins/metabolism
- STAT3 Transcription Factor/genetics*
- STAT3 Transcription Factor/metabolism
- Female
- Neoplasm Proteins/genetics*
- Neoplasm Proteins/metabolism
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Signal Transduction
- Glycogen Synthase Kinase 3/metabolism
- PubMed
- 23919497 Full text @ Biochem. J.
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.