Knockdown of EGR1 expression in PCa cells revealed it was required for the OCy-derived GDF15-mediated induction of in vitro PCa cell proliferation, migration and invasion.
We demonstrate using a PC model (DU145/RasB1) of bone and brain metastasis that EGR1 expression regulates angiogenic and osteoclastogenic properties of metastases.
Incidental support for the possibility of EGR1 being a regulator of hTERT expression in PCa was provided by i) immunolocalization of hTERT and EGR1 proteins in the same cell type (secretory epithelium) of PCa and BPH tissues; ii) significantly (p< 0.001) higher levels of both these proteins in CRPC (PC3 and DU145), compared with ADPC (LNCaP) cells.
Suppression of Egr-1 expression by siRNA abrogated the ability of TPA to induce Egr-1 and JNK-1 activities, moderately increasing the p21 activity and abrogating the anti-apoptotic effect of Egr-1 observed in the prostate cancer cell lines.
NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1).
Taken together, these results suggest that EGR-1 may stimulate prostate cancer cell growth through up-regulation of IGF-1R and indicate that down-regulation of EGR-1 could be an effective therapeutic approach against prostate cancer.
Our previous work has shown up-regulated mRNA of the transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS) in tissues adjacent to prostate cancer.
These results suggest that Egr-1 may promote prostate cancer development by modulating the activity of factors NF-κB and AP-1, which are involved in cell proliferation and apoptosis.
The current review focuses on the literature defining both differential Ca(2+) signaling and WT1/EGR1 expression patterns in 6 specific cancer subtypes: Acute Myeloid Leukemia, Wilms Tumor, breast cancer, ovarian cancer, glioblastoma and prostate cancer.
In addition, luciferase reporter gene assay showed that the transcriptional activity of AP-1 and NF-κB in PC-3 and LNCaP prostate carcinoma cell lines was also modulated by the overexpression of EGR-1 in these cells using tandem repeated Luc-AP-1 and Luc-NF-κB.
This led us to assign Egr-1, a transcription activator, as an inducer of hPar(1), and p53, a tumor suppressor gene, as an inhibitor, both acting to achieve fine tuning of hPar(1) in prostate carcinoma.
These studies highlight the importance for the Egr1 transcription factor in the hypoxic response in cultured prostate cancer cell lines, and indicate that the response of Egr1 is upstream of HIF-1 in these cells.
It is suggested that these defects in the suppressor network allow for the unopposed induction of TGFbeta1 and fibronectin, which favor transformation and survival of prostate tumor epithelial cells, and explain the role of Egr1 in prostate cancer.
Performing a supervised analysis to identify potential comarkers of PDGFR-beta in PCa, we identified a set of genes whose expression was associated with PDGFR-beta status including early growth response 1 (Egr1), an upstream effector of PDGF (4.2-fold upregulation), alpha-methylacyl-CoA racemase, as well as v-Maf and neuroblastoma suppressor of tumorigenicity (both with a 2.2-fold downregulation).
Taken together, bombesin-induced cyclin D1 expression in prostate cancer cells is mediated by Egr-1 activation and the interaction of Egr-1 with the Egr-1/Sp1 motif of the cyclin D1 promoter through the activation of MAPK pathway.
Moreover, multiple regression analysis revealed that up-regulation of EGR1 contributed significantly more to heparanase expression than did promoter CpG hypomethylation in prostate cancer samples (P < 0.0001).
Immunohistochemistry of human prostate cancer specimens demonstrated higher levels of EGR-1 in malignant cells located predominantly in the cytoplasm, whereas benign cells contained lower levels of EGR-1 located predominantly in the nucleus.