Journal Article

EGR1 regulates angiogenic and osteoclastogenic factors in prostate cancer and promotes metastasis

Beshiri, Michael L., Yin, JuanJuan, Alilin, Aian N., Kelly, Kathleen, Jansson, Keith H., Casey, Orla M., Lake, Ross G., Wang, Simeng, Ameri, Amir H., Agarwal, Supreet, Li, Lechen, Yang, Qi, Fang, Lei, Xu, Wanhai

2019

Overview

Early growth response-1 ( EGR1 ) is a transcription factor correlated with prostate cancer (PC) progression in a variety of contexts. For example, EGR1 levels increase in response to suppressed androgen receptor signaling or loss of the tumor suppressor, PTEN. EGR1 has been shown to regulate genes influencing proliferation, apoptosis, immune cell activation, and matrix degradation, among others. Despite this, the impact of EGR1 on PC metastatic colonization is unclear. We demonstrate using a PC model (DU145/RasB1) of bone and brain metastasis that EGR1 expression regulates angiogenic and osteoclastogenic properties of metastases. We have shown previously that FN14 (TNFRSF12A) and downstream NF-κB signaling is required for metastasis in this model. Here we demonstrate that FN14 ligation also leads to NF-κB-independent, MEK-dependent EGR1 expression. EGR1- depletion in DU145/RasB1 cells reduced both the number and size of metastases but did not affect primary tumor growth. Decreased EGR1 expression led to reduced blood vessel density in brain and bone metastases as well as decreased osteolytic bone lesion area and reduced numbers of osteoclasts at the bone–tumor interface. TWEAK (TNFSF12) induced several EGR1- dependent angiogenic and osteoclastogenic factors (e.g., PDGFA, TGFB1, SPP1, IL6, IL8, and TGFA, among others). Consistent with this, in clinical samples of PC, the level of several genes encoding angiogenic/osteoclastogenic pathway effectors correlated with EGR1 levels. Thus, we show here that EGR1 has a direct effect on prostate cancer metastases. EGR1 regulates angiogenic and osteoclastogenic factors, informing the underlying signaling networks that impact autonomous and microenvironmental mechanisms of cancer metastases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 14/5 / 38/43 / 38/61 / 38/89 / 59 / 59/5 / 631/67/322/803 / 631/80/304 / 82/1 / Adenocarcinoma - blood supply / Adenocarcinoma - genetics / Adenocarcinoma - pathology / Androgen receptors / Angiogenesis / Animals / Apoptosis / Bone cancer / Bone density / Bone lesions / Bone Neoplasms - genetics / Bone Neoplasms - secondary / Brain cancer / Care and treatment / Cell activation / Cell Biology / Colonization / Development and progression / Early Growth Response Protein 1 - genetics / Early Growth Response Protein 1 - physiology / EGR-1 protein / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Human Genetics / Humans / Interleukin 6 / Interleukin 8 / Internal Medicine / Male / Medicine / Medicine & Public Health / Metastases / Metastasis / Mice / Mice, Inbred NOD / Mice, Nude / Mice, SCID / Neoplasm Metastasis / Neovascularization, Pathologic - genetics / Neovascularization, Pathologic - pathology / NF-κB protein / Oncology / Osteoclasts / Osteogenesis - genetics / Osteolysis / PC-3 Cells / Platelet-derived growth factor / Prostate cancer / Prostatic Neoplasms - blood supply / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / PTEN protein / RAW 264.7 Cells / Signal Transduction - genetics / Transcription factors / Transforming growth factor-b1 / Tumor Cells, Cultured / Tumor Microenvironment - genetics / Tumor suppressor genes