ZEB2 blocking peptide

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 downregulation 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.

Background Human Schlafen 5 (SLFN5) has been reported to inhibit or promote cell invasion in tumours depending on their origin. However, its role in breast cancer (BRCA) is undetermined. Methods Differential expression analyses using The Cancer Genome Atlas (TCGA) data, clinical samples and cell lines were performed. Lentiviral knockdown and overexpression experiments were performed to detect changes in cell morphology, molecular markers and invasion. Chromatin immunoprecipitation-sequencing (ChIP-Seq) and luciferase reporter assays were performed to detect the SLFN5-binding motif. Results TCGA, clinical samples and cell lines showed that SLFN5 expression was negatively correlated with BRCA metastasis. SLFN5 knockdown induced epithelial-mesenchymal transition (EMT) and enhanced invasion in BRCA cell lines. However, overexpression triggered mesenchymal-epithelial transition (MET). SLFN5 inhibited the expression of ZEB1 but not ZEB2, SNAI1, SNAI2, TWIST1 or TWIST2. Knockdown and overexpression of ZEB1 indicated that it was a mediator of the SLFN5-governed phenotype and invasion changes. Moreover, SLFN5 inhibited ZEB1 transcription by directly binding to the SLFN5-binding motif on the ZEB1 promoter, but a SLFN5 C-terminal deletion mutant did not. Conclusion SLFN5 regulates reversible epithelial and mesenchymal transitions, and inhibits BRCA metastasis by suppression of ZEB1 transcription, suggesting that SLFN5 could be a potential target for BRCA therapy.