Abstract
Control of oncogenes, including ZEB1 and ZEB2, is a major checkpoint for preventing cancer, and loss of this control contributes to many cancers, including breast cancer. Thus tumour suppressors, such as FOXP3, which is mutated or lost in many cancer tissues, play an important role in maintaining normal tissue homeostasis. Here we show for the first time that ZEB2 is selectively down regulated by FOXP3 and also by the FOXP3 induced microRNA, miR-155. Interestingly, neither FOXP3 nor miR-155 directly altered the expression of ZEB1. In breast cancer cells repression of ZEB2, independently of ZEB1, resulted in reduced expression of a mesenchymal marker, Vimentin and reduced invasion. However, there was no de-repression of E-cadherin and migration was enhanced. Small interfering RNAs targeting ZEB2 suggest that this was a direct effect of ZEB2 and not FOXP3/miR-155. In normal human mammary epithelial cells, depletion of endogenous FOXP3 resulted in de-repression of ZEB2, accompanied by upregulated expression of vimentin, increased E-cadherin expression and cell morphological changes. We suggest that FOXP3 may help maintain normal breast epithelial characteristics through regulation of ZEB2, and loss of FOXP3 in breast cancer cells results in deregulation of ZEB2.
Highlights
A major cause of mortality in breast cancer patients is cancer metastasis [1], a key component of which is activation of epithelial-to mesenchymal transition (EMT) [2], in which cells lose epithelial features and acquire mesenchymal characteristics
Two proteins with well-established roles in regulating EMT are the transcription factors ZEB1 and ZEB2 [1, 4], high levels of which are associated with enhanced cell motility and invasion through the repression of genes including E-cadherin, which is required to maintain cellto cell contacts [4], and the induction of genes associated with mesenchymal characteristics including Vimentin [5], www.oncotarget.com an intermediate filament protein, which is required for the formation and function of invadopodia [6, 7] and is crucial for invasion
FOXP3 ChIP-on-chip studies performed in our lab [31] identified a region 68 kb downstream of the ZEB2 transcriptional start site (TSS) in Intron 2 of the ZEB2 gene that was significantly bound by FOXP3 (Figure 1A) indicating that ZEB2 was potentially directly regulated by FOXP3
Summary
A major cause of mortality in breast cancer patients is cancer metastasis [1], a key component of which is activation of epithelial-to mesenchymal transition (EMT) [2], in which cells lose epithelial features and acquire mesenchymal characteristics. Two proteins with well-established roles in regulating EMT are the transcription factors ZEB1 and ZEB2 [1, 4], high levels of which are associated with enhanced cell motility and invasion through the repression of genes including E-cadherin, which is required to maintain cellto cell contacts [4], and the induction of genes associated with mesenchymal characteristics including Vimentin [5], www.oncotarget.com an intermediate filament protein, which is required for the formation and function of invadopodia [6, 7] and is crucial for invasion. While some of the molecular mechanisms that control levels of both of the ZEB proteins have been documented [15,16,17,18], there are new tumour suppressor candidates implicated in the control of ZEB1 and ZEB2 Identifying these regulatory mechanisms will provide important new insights into how these proteins become over-expressed in cancer progression. More recently FOXP3 has emerged as a tumour suppressor in breast [23,24,25,26,27,28,29] and prostate [28, 30] epithelia, repressing a number of oncogenes including c-myc [30], Ezh2 [25], HER-2/ErbB2 [23] SKP2 [24] and SATB1 [26], while up regulating expression of tumour suppressors p21 [27] and LATS2 [28]
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