Twist1 and AP-1 cooperatively upregulate integrin α5 expression to induce invasion and the epithelial–mesenchymal transition

Abstract

Epithelial-mesenchymal transition (EMT) is an important process implicated in tumor invasion and metastasis. Twist1 is a transcription factor that induces EMT, including E-cadherin suppression and cancer cell migration and invasion; hence it promotes cancer metastasis. Twist1 directly or indirectly regulates the expression of various genes and cellular functions involved in cancer progression. However, the underlying mechanisms remain largely unknown. In this study, we investigated the molecular basis for Twist1-mediated invasion and EMT. In human cancer cells, Twist1 was found to directly upregulate transcription of the mesenchymal gene integrin α5 in an E-box-independent, but activating protein-1 (AP-1) element-dependent, manner. Twist1 activated the integrin α5 promoter by interacting with and activating the transcription factor AP-1, composed of c-Jun and activating transcription factor-2 (ATF-2); it also enhanced the nuclear presence of ATF-2. AP-1 was critical for Twist1-induced cancer cell invasion, primarily through the induction of integrin α5, which activated c-Jun N-terminal kinase and focal adhesion kinase-signaling activities. Using data from The Cancer Genome Atlas, we found that Twist1 expression positively correlates with integrin α5 expression in human colorectal cancers. These findings suggest that cooperation between Twist1 and AP-1 represents a novel mechanism for EMT and tumor invasiveness. This study supports further investigation into the molecular basis underlying the diverse Twist1-mediated functions that occur during tumor progression.

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

“…On the other hand, we previously reported that ZEB2 directly interacts/cooperates with Sp1 to function as a transcriptional activator of mesenchymal genes (vimentin, integrin α5, and cadherin-11) to induce invasion [53]. We also found that functional cooperation between Twist1 and AP-1 induces EMT and invasion [54]. …”

Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner

“…The EMT is characterized by morphological changes from epithelial to spindle-shaped mesenchymal like cells, increased cell size, loss of cell adhesion as consequence of changes in integrin expression, in particular α 5 β 1 overexpression [15], increased invasiveness and expression of mesenchymal markers especially vimentin [32, 33]. CPS has been found to induce EMT in colon cancer cells [16], but no data on BC has been provided so far.…”

“…EMT, characterized by morphological and molecular changes of cancer cells with increase of mesenchymal-related proteins, plays a pivotal role in the acquisition of malignant features such as invasion, metastasis and chemoresistance [14, 15]. In this regard, CPS induces EMT in colon cancer cells by modulating the reactive oxygen species (ROS) production and the AKT/mTOR pathways [16].…”

Knockdown of BC200 RNA expression reduces cell migration and invasion by destabilizing mRNA for calcium-binding protein S100A11

“…41 For invasion assays, cells (50,000 per well) were plated in serum-free medium on 24-well trans-well inserts (Costar) coated with 100 ml/well of Matrigel (BD Biosciences, #354234, 250 mg/ml) and 100 ml/well of collagen I (the underside; Sigma, C7661, 20 mg/ml). When mitomycin C (Sigma, M4287, 1 mg/ ml) was added, FBS-containing medium was used instead of serum-free medium.…”