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)

Abstract

Genes involved in normal developmental processes attract attention as mediators of tumour progression as they facilitate migration of tumour cells. EMT (epithelial–mesenchymal transition), an essential part of embryonic development, tissue remodelling and wound repair, is crucial for tumour metastasis. Previously, zinc transporter ZIP6 [SLC39A6; solute carrier family 39 (zinc transporter), member 6; also known as LIV-1) was linked to EMT in zebrafish gastrulation through a STAT3 (signal transducer and activator of transcription 3) mechanism, resulting in nuclear localization of transcription factor Snail. In the present study, we show that zinc transporter ZIP6 is transcriptionally induced by STAT3 and unprecedented among zinc transporters, and is activated by N-terminal cleavage which triggers ZIP6 plasma membrane location and zinc influx. This zinc influx inactivates GSK-3β (glycogen synthase kinase 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 (epithelial 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-dependent mechanism of tumour metastasis.

Paradoxical zinc toxicity and oxidative stress in the mammary gland during marginal dietary zinc deficiency

“…However, both glucose and calcium signaling also increase ZIP6 expression [54], and thus other regulatory factors cannot be ruled out. Recent work by Hogstrand et al [55] found that ZIP6 over-expression drives cell motility and promotes epithelial-to-mesenchymal transition in MCF7 breast cancer cells. In contrast, ZIP6 over-expression is associated with better prognosis in ER + breast disease [31], and our previous work found that repressing ZIP6 expression in ER + tumorigenic T47D breast cancer cells promotes epithelial-to-mesenchymal transition [56].…”

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

“…In the case of gastric cancer, the involvement of STAT3 in the resistance to treatment has been reported in the literature [52][53][54][55][56]. Furthermore, this resistance is associated with the activation of Stat3 and EMT [19,57]. The molecular interaction of STAT3 and Snail, ZIP6, and also the other transcription factors suggests that it is part of a core that controls EMT in normal and pathological conditions [58,59].…”

“…A recent study indicates the involvement of Stat3 in the epithelial-to-mesenchymal transition (EMT) by way of a mechanism that leads to the nuclear localization of Snail, a transcriptional repressor for E-cadherin 1 (CDH1). This causes a change in the cellular phenotype, as the cells become round, loose intercellular contact and acquire invasive capabilities [19]. The involvement of Stat3 in EMT, followed by an increased invasion and metastasis of tumor cells, has been reported in cases of breast and prostate cancer [20][21][22].…”

Differential expression of zinc transporters accompanies the differentiation of C2C12 myoblasts

“…ZIP5 is required for systemic Zn excretion and to promote the development of the sclera and retina [30–32]. Zip6 over-expression has been associated with the epithelial-mesenchymal transition of different cancer types [33–37]. ZIP6 also contributes to dendritic cell maturation [38].…”