He Y, Northey J J, Pelletier A, Kos Z, Meunier L, Haibe-Kains B, Mes-Masson A-M, Côté J-F, Siegel P M, Lamarche-Vane N
Cancer Research Program, Research Institute of the McGill University Health Center, Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
Oncogene. 2017 Jun 15;36(24):3490-3503. doi: 10.1038/onc.2016.492. Epub 2017 Jan 30.
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.
E-钙黏蛋白的缺失会导致细胞间连接机制功能失调，这是上皮-间质转化（EMT）的起始步骤，促进癌细胞侵袭和转移形成。一组E-钙黏蛋白（CDH1）基因表达的转录抑制因子，包括Snail1、Snail2和Zeb2，介导乳腺癌中E-钙黏蛋白的下调。然而，乳腺癌进展过程中E-钙黏蛋白表达调控的分子机制仍 largely未知。在这里，通过使用全基因组表达方法，我们揭示了Cdc42 GTP酶激活蛋白（CdGAP）在调控EMT相关基因表达中的新功能。我们发现CdGAP利用其富含脯氨酸的结构域与Zeb2形成功能复合物，以介导ErbB2转化的乳腺癌细胞中E-钙黏蛋白表达的抑制。相反，CdGAP表达的敲低导致转录抑制因子Snail1和Zeb2减少，这与E-钙黏蛋白水平增加、细胞间连接恢复以及上皮样形态变化相关。在体内，ErbB2转化的乳腺癌细胞中CdGAP的缺失损害肿瘤生长并抑制肺转移。最后，CdGAP在基底型乳腺癌细胞中高表达，其强表达与乳腺癌患者的不良预后相关。总之，这些数据支持CdGAP以前未知的核功能，即它以不依赖GAP的方式与转录抑制因子合作，通过抑制E-钙黏蛋白转录作为乳腺癌的关键调节因子。靶向Zeb2-CdGAP相互作用可能代表乳腺癌治疗的新治疗机会。
