The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer

Abstract

Elucidating the mechanisms that underlie metastasis is of paramount importance to understanding tumor progression and to the development of novel therapeutics. Epithelial to Mesenchymal Transition (EMT) plays a vital role in tumor cell dissemination and is regulated by a core cassette of transcription factors. Despite recent advances, the molecular pathways that regulate the EMT program have not yet been fully delineated. We show that Siah ubiquitin ligases regulate Zeb1 protein, a key EMT transcription factor. The induction of EMT in breast cancer cells leads to the down-regulation of Siah, while the loss of Siah induces a mesenchymal phenotype, concurrent with an up-regulation of Zeb1. Overexpression of Siah in vitro mediates Zeb1 degradation, which can be blocked with a Siah peptide inhibitor. Thus, this work demonstrates that Siah is a novel regulator of EMT. This work is the first to identify a mechanism of post-translational regulation of the key Epithelial to Mesenchymal Transition transcription factor Zeb1.

The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers

“…This observation may be explained by the fact that SIAH2 is able to promote the proteasomal degradation of SIAH1 [34]. Moreover, the attenuation of SIAH1 by RNAi leads to an upregulation of SIAH2 mRNA expression in MCF-7 cells [35]. It is hence possible that SIAH1 and SIAH2 control each other at various levels.…”

“…[10] TNF-a/TGF-b MCF-7 and NMuMG cells (murine epithelial cell line) SIAH1 and SIAH2 [35] The genes encoding for the seven in absentia homologues SIAH1 and SIAH2 are induced by the tumor suppressor p53, which is inactivated in a large number of cancer specimens. Furthermore, the SIAH2 gene is induced independent of de novo protein synthesis by the ligand-bound ER and by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).…”

“…These include cytokine signaling modulating the epithelial to mesenchymal transition (EMT) during the formation of metastases [45]. The induction of EMT in human breast cancer cells and in murine mammary epithelial cells by tumor necrosis factor alpha (TNF-a) plus transforming growth factor beta (TGF-b) or TGF-b, respectively, caused a loss of SIAH1 and SIAH2 proteins without influencing SIAH1 and SIAH2 mRNA levels [35]. Remarkably, RNAi-mediated reduction of SIAH1 or SIAH2, as well as the genetic elimination of SIAH2, led to an induction of mesenchymal gene expression patterns in breast cancer cells [35].…”

“…The induction of EMT in human breast cancer cells and in murine mammary epithelial cells by tumor necrosis factor alpha (TNF-a) plus transforming growth factor beta (TGF-b) or TGF-b, respectively, caused a loss of SIAH1 and SIAH2 proteins without influencing SIAH1 and SIAH2 mRNA levels [35]. Remarkably, RNAi-mediated reduction of SIAH1 or SIAH2, as well as the genetic elimination of SIAH2, led to an induction of mesenchymal gene expression patterns in breast cancer cells [35]. It has been found that a key proximal mediator of EMT, the transcription factor Zinc finger E-box binding homeobox-1 (ZEB1) [45] is targeted for proteasomal degradation by SIAH1 and SIAH2 [35].…”

“…Remarkably, RNAi-mediated reduction of SIAH1 or SIAH2, as well as the genetic elimination of SIAH2, led to an induction of mesenchymal gene expression patterns in breast cancer cells [35]. It has been found that a key proximal mediator of EMT, the transcription factor Zinc finger E-box binding homeobox-1 (ZEB1) [45] is targeted for proteasomal degradation by SIAH1 and SIAH2 [35]. As EMT can also promote chemo-and radioresistance [45], it will be interesting to see whether SIAHs control such processes via the EMT.…”