The Cdc42/Rac1 regulator CdGAP is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer

Abstract

The loss of E-cadherin causes dysfunction of the cell-cell junction machinery, which is an initial step in epithelial-to-mesenchymal transition (EMT), facilitating cancer cell invasion and the formation of metastases. A set of transcriptional repressors of E-cadherin (CDH1) gene expression, including Snail1, Snail2 and Zeb2 mediate E-cadherin down-regulation in breast cancer. However, the molecular mechanisms underlying the control of E-cadherin expression in breast cancer progression remain largely unknown. Here, by using global gene expression approaches, we uncover a novel function for Cdc42 GTPase-activating protein (CdGAP) in the regulation of expression of genes involved in EMT. We found that CdGAP used its proline-rich domain to form a functional complex with Zeb2 to mediate the repression of E-cadherin expression in ErbB2-transformed breast cancer cells. Conversely, knockdown of CdGAP expression led to a decrease of the transcriptional repressors Snail1 and Zeb2, and this correlated with an increase in E-cadherin levels, restoration of cell-cell junctions, and epithelial-like morphological changes. In vivo, loss of CdGAP in ErbB2-transformed breast cancer cells impaired tumor growth and suppressed metastasis to lungs. Finally, CdGAP was highly expressed in basal-type breast cancer cells, and its strong expression correlated with poor prognosis in breast cancer patients. Together, these data support a previously unknown nuclear function for CdGAP where it cooperates in a GAP-independent manner with transcriptional repressors to function as a critical modulator of breast cancer through repression of E-cadherin transcription. Targeting Zeb2-CdGAP interactions may represent novel therapeutic opportunities for breast cancer treatment.

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

“…Interestingly, CdGAP is required for TGFβ and Neu/ErbB2-induced cell motility and invasion independently of its GAP activity. Through its proline-rich domain, CdGAP forms a functional complex with the transcription factor Zeb2, leading to repression of E-cadherin, and thus favoring epithelial-to-mesenchymal transition (EMT) (54). Another intriguing example is p190B RhoGAP, whose overexpression in the mammary gland results in Rac1 activation and enhanced ErbB2-driven tumorigenesis and metastasis (55).…”

Death Domain-Associated Protein Promotes Colon Cancer Metastasis through Direct Interaction with ZEB1

“…E-cadherin is a key factor in cell-cell adhesion. The destruction of E-cadherin is thought to be one of the first steps in metastasis, playing critical roles in tumor metastasis [21,[31][32][33]. Recent reports have shown that a decrease in E-cadherin is strongly associated with metastasis and poor clinical prognosis and suggested that targeting E-cadherin could be a promising therapeutic approach for metastatic CRC [34].…”

“…[35]. ZEB proteins, which are a family of transcription factors, have also been shown to directly bind to the promoter of E-cadherin and suppress its expression at the transcriptional level [21]. DAXX can directly bind to many transcription factors and act as a potent transcriptional repressor [10].…”

“…However, the regulation of E-cadherin remains poorly understood. In various cancer types, studies have shown that ZEB proteins can directly bind to the promoter of E-cadherin and suppress its expression at the transcriptional level [21]. Further, studies have shown that DAXX can markedly inhibit several transcription factorresponsive reporters, including E2F1, Sp1, and NF-κB [10], but the mechanisms of such regulation have not been clearly demonstrated.…”

Current opinion in the molecular genetics of Adams-Oliver syndrome

“…[7] Of interest, ARHGAP31 has recently been discovered to exhibit transcriptional activity, which is absent in the recurrent p.GlnQ683* nonsense variant, leading to the possibility of potential crosstalk between ARHGAP31 and the Notch signalling pathway. [28] The NOTCH1 extracellular domain is composed of 36 EGF-like repeats, which are modified by posttranslational glycosylation with O-glycan residues. Examination of glycosyltransferase activity in mutant EOGT proteins in vitro has suggested that AOS may be caused by defective O-GlcNAcylation in the endoplasmic reticulum.…”