Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Abstract

Anoikis (detachment-induced apoptosis) prevents the survival of cells at inappropriate sites of the body and can therefore act as a barrier to metastasis. In a functionbased genome-wide screen, we have previously identified the neurotrophic tyrosine kinase receptor TrkB as a potent suppressor of anoikis. Consistently, activated TrkB oncogenically transforms non-malignant epithelial cells and causes them to invade and produce metastatic tumors in vivo. Overexpression of activated TrkB also results in morphological transformation, resembling epithelial-mesenchymal transition (EMT). E-cadherin, an important EMT regulator, and two E-cadherin repressors, Twist and Snail, are critical for these TrkB functions. As Snail has been shown to induce Zeb1, another E-cadherin repressor, we hypothesized that Zeb1 could be a TrkB target, too. We show here that Zeb1 is required for TrkB-induced EMT in epithelial cells, as RNAi-mediated knockdown of Zeb1 reverted the morphological changes induced by TrkB. Furthermore, Zeb1 is involved in TrkB-induced anoikis resistance, migration and invasion. In vivo, knockdown of Zeb1 strongly reduced TrkB-induced metastasis. Finally, epistasis experiments showed that Zeb1 acts downstream of Twist and Snail. We conclude that Zeb1 is required for several TrkB-induced effects in vitro and in vivo, including metastasis.

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

“…However, it has been demonstrated that Snail induces ZEB1 (ref. 47), implying a possible link between Snail and ZEB1 in Pten repression, at least under some conditions. Although various mechanisms, including induction of microRNAs (miRNAs) such as mir21 that target Pten mRNA, have been put forth as a mechanism of Pten repression by TGF-b 24,45 , we wondered whether induction of ZEB1 might also be mediating TGF-b repression of Pten.…”

Regulation of the MicroRNA 200b (miRNA-200b) by Transcriptional Regulators PEA3 and ELK-1 Protein Affects Expression of Pin1 Protein to Control Anoikis

“…Following reduced expression of E-cadherin, cancer cells are easily detached from the primary tumor to promote metastasis. However, detachment from the primary tumor also results in loss of interaction with the matrix and induction of anoikis, which is believed to act as a barrier to metastasis (45,46). Resistance to anoikis may allow survival of cancer cells during systemic circulation, thereby facilitating secondary tumor formation in distant organs (47)(48)(49).…”

Anoikis: an emerging hallmark in health and diseases

“…Furthermore, TrkB over-expression results in EMT via the induction of Twist and Snail [129]. Snail is able to induce also ZEB1, another transcription factor which suppresses E-cadherin [130]. An intriguing feedback loop between ZEB transcription factors and members of the miR200 family [131] in controlling EMT, anoikis resistance and metastasis has been recently elucidated [132].…”