The Presence of Androgen Receptor Elements Regulates ZEB1 Expression in the Absence of Androgen Receptor

Abstract

Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor that plays a central role in the epithelial to mesenchymal transition (EMT) of cancer cell lines. Studies on its regulation have mostly focused on the negative 3’UTR binding of miR200c. Interestingly, it has been previously reported that androgen receptor (AR) regulates ZEB1 expression in breast and prostate cancers. In order to validate this, various ZEB1 promoter deletions were cloned into a luciferase reporter system to elucidate the contribution of two putative androgen response elements (AREs). The in vivo contribution of AR was also assessed in cell lines after R1881 treatment using qPCR with prostate specific antigen (PSA) as the positive control. We discovered that AR upregulates the levels of expression of ZEB1 10-fold on a luciferase promoter that only contains the distal ARE. However, when the proximal ARE is included, no additional activation is apparent with AR or its hormone independent variant, AR-V7. Furthermore, we demonstrate here that a promoter construct containing both AREs activates transcription of ZEB1 even in the AR-null cell lines DU145 and PC3. Incubation of the AR-positive cell line, LNCaP with R1881, failed to substantially increase the expression levels of ZEB1. Despite the presence of AREs in the promoter region, it appears that ZEB1 expression can be induced even without AR. In addition, the region around the distal ARE is a potent repressor in AR-null cell lines.

The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

“…C, D). Molecular changes can vary depending on the cancer type, location, and the individual; however, loss of CDH1 expression is used as the gold standard for EMT [Mooney et al, ]. CDH1 encodes the single pass, transmembrane glycoprotein, E‐cadherin.…”

Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins

“…Epithelial–mesenchymal transition (EMT) and its reverse mesenchymal–epithelial transition (MET) that appear to be closely associated with metastasis6 and the acquisition of stem-cell properties by cancer cells7 are the classical examples of phenotypic plasticity in biological systems. EMT, first discovered by Greenburg and Hay,8 is, in fact, a normal process in development and wound healing, in which epithelial cells undergo multiple biochemical changes that enable them to assume a mesenchymal phenotype which includes a loss of apico-basal polarity and cell-cell attachments to gain migratory capacity, invasiveness, and increased resistance to apoptosis 910…”

miR‐200c regulates endothelin‐1 induced PASMCs abnormal proliferation and apoptosis

“…microRNAs (miRNAs) are noncoding RNAs that negatively regulate gene expression by binding to the 3′‐untranslated regions (3′‐UTR) of their target messenger RNA (mRNA) and consequently suppressing translation and/or degrading mRNA transcripts . miR‐200c is a negative regulator of GATA binding protein 4 (GATA4) to induce apoptosis of human embryonic stem cells . Zinc finger E‐box binding homeobox1 (ZEB‐1) is a transcription factor that plays crucial roles in the epithelial to mesenchymal transition of cancer cell .…”

“…miR‐200c is a negative regulator of GATA binding protein 4 (GATA4) to induce apoptosis of human embryonic stem cells . Zinc finger E‐box binding homeobox1 (ZEB‐1) is a transcription factor that plays crucial roles in the epithelial to mesenchymal transition of cancer cell . Most studies focused on miR‐200c regulation by the negative 3′‐UTR binding .…”