Androgen up-regulation of Twist1 gene expression is mediated by ETV1

Abstract

Twist1, a basic helix-loop-helix transcription factor that regulates a number of genes involved in epithelial-to-mesenchymal transition (EMT), is upregulated in prostate cancer. Androgen regulation of Twist1 has been reported in a previous study. However, the mechanism of androgen regulation of the Twist1 gene is not understood because the Twist1 promoter lacks androgen receptor (AR)-responsive elements. Previous studies have shown that the Twist1 promoter has putative binding sites for PEA3 subfamily of ETS transcription factors. Our lab has previously identified Ets Variant 1 (ETV1), a member of the PEA3 subfamily, as a novel androgen-regulated gene that is involved in prostate cancer cell invasion through unknown mechanism. In view of these data, we hypothesized that androgen-activated AR upregulates Twist1 gene expression via ETV1. Our data confirmed the published work that androgen positively regulates Twist1 gene expression and further showed that this positive effect was directed at the Twist1 promoter. The positive effect of androgen on Twist1 gene expression was abrogated upon disruption of AR expression by siRNA or of AR activity by Casodex. More importantly, our data show that disruption of ETV1 leads to significant decrease in both androgen-mediated upregulation as well as basal level of Twist1, which we are able to rescue upon re-expression of ETV1. Indeed, we are able to show that ETV1 mediates the androgen upregulation of Twist1 by acting on the proximal region of Twist1 promoter. Additionally, our data show that Twist1 regulates prostate cancer cell invasion and EMT, providing a possible mechanism by which ETV1 mediates prostate cancer cell invasion. In conclusion, in this study we report Twist1 as an indirect target of AR and androgen regulation through ETV1.

Androgen receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1 nonsense-mediated decay through lncRNA-TANAR

“…A previous study revealed that AR could upregulate TWIST1 via ETV1 in prostate cancer [ 45 ]. Similarly in RCC cells, AR can also increase TWIST1 expression through an indirect mechanism through lncRNA-TANAR to impact RCC VM development.…”

MicroRNA-149 suppresses osteogenic differentiation of mesenchymal stem cells via inhibition of AKT1-dependent Twist1 phosphorylation

“…Besides, AKT1 is capable of enhancing the phosphorylation of twist family bHLH transcription factor 1 (Twist1), which is required for β-TrCP-mediated Twist1 ubiquitination and degradation [ 15 ]. Twist1, an essential helix-loop-helix transcription factor, is known to regulate numerous genes related to epithelial-to-mesenchymal transition [ 16 ]. In addition, previous research illustrated that the methylation of DNA in the promoter region of Twist1 was a crucial mechanism in osteoblastic differentiation of MSCs [ 17 ].…”

HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET

“…ETV1 binds to many target genes and plays a role in tumor progression and metastasis by regulating expression of them. It has previously been shown to confer the aggressive biologic behavior of tumors via inhibition of checkpoint kinase 1 (CHK1), upregulation of EMT-associated genes such as TWIST1, SNAIL, HAS2, pro-metastatic genes such as MMP1/7, SPARC , methyltransferase METTL3 [20,[49][50][51][52][53]. Herein, we uncovered that PTK2 and c-MET were transcriptional targets of ETV1.…”