Loss of EGR3 is an independent risk factor for metastatic progression in prostate cancer


Identification of pro-metastatic genomic alterations is urgently needed to help understand and prevent the fatal course of prostate cancer. Here, we found that the transcription factor EGR3, located at chromosome 8p21.3, is a critical metastasis suppressor. Aberrant deletion of EGR3 was found in up to 59.76% (deep deletions, 16.87%; shallow deletions, 42.89%) of prostate cancer patients. In informatics analysis, EGR3 loss was associated with prostate cancer progression and low survival rates. EGR3 expression inversely correlated with the expressions of epithelial-to-mesenchymal transition (EMT) and metastasis-related gene sets in prostate cancer tissues. In prostate cancer cells, EGR3 blocked the EMT process and suppressed cell migration and invasion. In a mouse model for cancer metastasis, EGR3 overexpression significantly suppressed bone metastases of PC3 and 22Rv1 prostate cancer cells. Mechanistically, EGR3 transcriptionally activated ZFP36, GADD45B, and SOCS3 genes by directly binding to their promoter regions. The EMT-inhibitory and tumor-suppressive roles of the EGR3 downstream genes were identified through in vitro and in silico analyses. Together, our results showed that EGR3 may be a biomarker to predict clinical outcomes and that it plays an important role in the metastatic progression of prostate cancer.

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Fig. 1: EGR3 deletion in prostate cancer patients.
Fig. 2: EGR3 protein levels are reduced in advanced prostate cancer and inversely correlate with patient survival.
Fig. 3: EGR3 expression negatively correlates with EMT and metastasis of prostate cancer.
Fig. 4: EGR3 inhibits EMT, migration, and invasion of prostate cancer cells.
Fig. 5: Transwell migration and invasion assays of prostate cancer cells.
Fig. 6: EGR3 represses bone metastasis of prostate cancer cells in vivo.
Fig. 7: EGR3 directly transactivates ZFP36, GADD45B, and SOCS3 genes to suppress EMT and cell migration.
Fig. 8: Clinical significance of EGR3 downstream target genes.


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The authors acknowledge the contribution of all the investigators at the participating study sites. This work was supported by the National Research Foundation of Korea (2019R1A2B5B03069677 and 2020R1A4A2002903).

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JWP and SHS designed the study. SHS, IK, JEL, and JWP wrote and revised the paper. SHS, IK, JEL, and ML performed cell-based experiments and analyzed biochemical data. SHS, IK, and JEL analyzed informatics.

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Correspondence to Jong-Wan Park.

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Shin, S., Kim, I., Lee, J.E. et al. Loss of EGR3 is an independent risk factor for metastatic progression in prostate cancer. Oncogene 39, 5839–5854 (2020). https://doi.org/10.1038/s41388-020-01418-5

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