A novel mechanism driving poor-prognosis prostate cancer: Overexpression of the DNA repair gene, ribonucleotide reductase small subunit M2 (RRM2)

Purpose: Defects in genes in the DNA repair pathways Results: Knockdown of RRM2 inhibited its oncogenic significantly contribute to prostate cancer progression. We function, whereas overexpression of RRM2 promoted hypothesize that overexpression of DNA repair genes may epithelial mesenchymal transition in prostate cancer cells. also drive poorer outcomes in prostate cancer. The ribonucle-The prognostic value of RRM2 RNA levels in prostate cancer otide reductase small subunit M2 (RRM2) is essential for DNA was confirmed in 11 clinical cohorts. Integrating the tran-synthesis and DNA repair by producing dNTPs. It is frequently scriptomic and phosphoproteomic changes induced by overexpressed in cancers, but very little is known about its RRM2 unraveled multiple oncogenic pathways downstream function in prostate cancer. of RRM2. Targeting RRM2 with COH29 showed excellent Experimental Design: The oncogenic activity of RRM2 in efficacy. Thirteen putative RRM2-targeting transcription fac-prostate cancer cells was assessed by inhibiting or overexpres-tors were bioinformatically identified, and FOXM1 was sing RRM2. The molecular mechanisms of RRM2 function were validated to transcriptionally activate RRM2 in prostate determined. The clinical significance of RRM2 overexpression cancer. was evaluated in 11 prostate cancer clinical cohorts. The efficacy Conclusions: We propose that increased expression of of an RRM2 inhibitor (COH29) was assessed in vitro and in vivo. RRM2 is a mechanism driving poor patient outcomes in Finally, the mechanism underlying the transcriptional activa-prostate cancer and that its inhibition may be of significant tion of RRM2 in prostate cancer tissue and cells was determined. therapeutic value.