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

Oncogene volume 38, pages 6241–6255 (2019)Cite this article

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Abstract

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.

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and National Natural Science Foundation of China (81270022, 81611130070, and 81771898; to WX).

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Authors and Affiliations

  1. Department of Urology, the Fourth Hospital of Harbin Medical University, Harbin Heilongjiang, China

    Lechen Li & Wanhai Xu

  2. Laboratory of Genitourinary Cancer Pathogenesis, CCR, National Cancer Institute, Bethesda, MD, USA

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

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Li, L., Ameri, A.H., Wang, S. et al. EGR1 regulates angiogenic and osteoclastogenic factors in prostate cancer and promotes metastasis. Oncogene 38, 6241–6255 (2019). https://doi.org/10.1038/s41388-019-0873-8

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