Cooperation between ZEB2 and Sp1 promotes cancer cell survival and angiogenesis during metastasis through induction of survivin and VEGF

Abstract

Epithelial-mesenchymal transition (EMT) is a process implicated in tumor invasion and metastasis. During EMT, epithelial cells undergo molecular changes to acquire mesenchymal phenotypes, which are mediated by EMT-inducing transcription factors. Previously, we showed that ZEB2 cooperates with the transcription factor Sp1 to function as a transcriptional activator of vimentin, integrin alpha 5, and cadherin-11, which promotes cancer cell invasion. We hypothesized that ZEB2, through cooperation with Sp1, would mediate diverse cellular functions beyond EMT and invasion during metastasis. ZEB2 upregulated the expression of Sp1-regulated genes such as survivin, bcl-2, cyclin D1, and vascular endothelial growth factor in an Sp1-dependent manner, resulting in increased cancer cell survival and proliferation and endothelial cell activation in vitro, and increased circulating tumor cell survival and tumor angiogenesis in vivo. In addition, Sp1 enhanced ZEB2 stability, suggesting the presence of a positive feedback loop between ZEB2 and Sp1. Clinical data showed that ZEB2 expression was positively associated with Sp1 expression, and that the expression of both of these factors had prognostic significance for predicting survival in cancer patients. This study suggests that invasion is linked to cancer cell survival and angiogenesis by ZEB2 during cancer progression, and increases our understanding of the pathways via which EMT-inducing transcription factors regulate the complex process of metastasis.