ZEB2 upregulates integrin α5 expression through cooperation with Sp1 to induce invasion during epithelial–mesenchymal transition of human cancer cells

Abstract

Epithelial-mesenchymal transition (EMT) is a process implicated in tumor invasion, metastasis, embryonic development and wound healing. ZEB2 is a transcription factor involved in EMT that represses E-cadherin transcription. Although E-cadherin downregulation is a major event during EMT and tumor progression, E-cadherin reduction is probably not sufficient for full invasiveness. The mechanisms by which E-cadherin transcriptional repressors induce mesenchymal genes during EMT remain largely unknown. Here, we investigated the role of ZEB2 in the induction of integrin α5 during cancer EMT and its underlying mechanism. In human cancer cells, ZEB2 was found to directly upregulate integrin α5 transcription in a manner that is independent of the regulation of E-cadherin expression. Conversely, depletion of ZEB2 by small interfering RNA suppressed integrin α5 expression, leading to reduced invasion. Suppression of integrin α5 inhibited cancer cell invasion, suggesting an important role for integrin α5 in cancer progression. Furthermore, ZEB2 was found to activate the integrin α5 and vimentin promoters by interacting with and activating the transcription factor Sp1, suggesting that cooperation between ZEB2 and Sp1 represents a novel mechanism of mesenchymal gene activation during EMT. These findings increase our understanding of the pathways beyond E-cadherin reduction that regulate mesenchymal gene expression during EMT and cancer progression.

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

“…Lu et al have shown that miRNA-19a, which is associated with cancer invasion and metastasis and is expressed highly in gastric cancer cell lines, induces EMT in gastric cancer cells by activating the PI3K/AKT signal pathway (33 (12). Previous study by Nam and colleagues on cancer cell EMT has shown that Sp1 plays crucial roles in the integrin α5-dependent induction of EMT and metastasis (8). Given these findings, we sought to determine whether Sp1 is involved in the EMT of gastric cancer, and whether abnormal expression of Sp1 in gastric cancer EMT, invasion and metastasis is regulated in a post-transcriptional manner.…”

“…In cancer growth and metastasis, Sp1 influences a variety of cancer cell types through the regulation of oncogenes, tumor suppressor genes, cell cycle regulators, growth related signal transduction pathways, angiogenic factors and apoptosis (5,6). Sp1 is expressed at high levels in many cancers (7) and is closely associated with EMT (8,9). New therapies targeting Sp1 could, therefore, represent beneficial additions to current clinical chemotherapy strategies.…”

The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection

“…Indeed, there are reports that ZEB2 can act as a transcriptional activator when complexed with SP1, driving the expression of vimentin and integrin α-5 in certain cancer cell lines without directly binding DNA (Bindels et al, 2006;Nam et al, 2012). …”

Silencing of COX-2 by RNAi Modulates Epithelial-Mesenchymal Transition in Breast Cancer Cells Partially Dependent on the PGE2Cascade

“…Several transcription factors have been characterized as transcriptional repressors of E-cadherin and are implicated in promoting EMT in tumor progression: the Snail superfamily of zinc-finger factors (Snail and Slug), the ZEB family (ZEB1 and ZEB2) and basic helix-loop-helix factors (Twist, E47 and TCF4) (Li et al, 2011;Nam et al, 2012). The mechanisms through which these repressors downregulate E-cadherin and other epithelial genes during EMT are fairly well established.…”