Prostate cancer is a major global health concern with limited treatment options for advanced disease. Its heterogeneity challenges the identification of crucial driver genes implicated in disease progression. Activating protein-1 (AP-1) transcription factor is associated with cancer since the first identification of its subunits, the proto-oncogenes JUN and FOS. Whereas both JUN and FOS have been implicated in prostate cancer, this study provides the first functional evidence that FOS acts as a tumor suppressor during prostate cancer progression and invasion. Data mining revealed decreased FOS expression in prostate cancer and a further downregulation in metastatic disease, consistent with FOS expression in cell lines derived from different prostate cancer stages. FOS deficiency in prostate cancer cell lines increases cell proliferation and induces oncogenic pathway alterations. Importantly, in vivo CRISPR/Cas9-mediated Fos and Pten double mutation in murine prostate epithelium results in increased proliferation and invasiveness compared to the abrogation of Pten alone. Interestingly, enhanced Jun expression is observed in the murine prostatic intraepithelial neoplasia lacking Fos. CRISPR/Cas9-mediated knockout of Jun combined with Fos and Pten deficiency diminishes the increased proliferation rate in vivo but not the ability to form invasive disease. Overall, we demonstrate that loss of Fos promotes disease progression from clinical latent prostate cancer to advanced disease through accelerated proliferation and invasiveness, partly through Jun.
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We thank Mette Simonsen for assistance with PET/MRI scanning. This work was funded by Danish cancer society (R146-A9394 and R204-A12490), Ministry of health (4-1612-236/7), AUFF NOVA (E-2o15-FLS-9-8), Dagmar Marshalls Fond, Einar Willumsens Mindelegat, Harboefonden, Helge Peetz og Verner og hustru Vilma Peetz legat, Raimond og Dagmar Ringgåed-Bohns Fond, The Aarhus University Research Foundation, and Thora og Viggo Grove’s Mindelegat (all to MKT). EFW and LB are supported by the European Research Council (grant: ERC‐AdG 2016 CSI‐Fun-741888 to EFW) and the Medical University of Vienna.
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Riedel, M., Berthelsen, M.F., Cai, H. et al. In vivo CRISPR inactivation of Fos promotes prostate cancer progression by altering the associated AP-1 subunit Jun. Oncogene 40, 2437–2447 (2021). https://doi.org/10.1038/s41388-021-01724-6