A Novel Mechanism Driving Poor-Prognosis Prostate Cancer: Overexpression of the DNA Repair Gene, Ribonucleotide Reductase Small Subunit M2 (RRM2).

Abstract

PURPOSE:

Defects in genes in the DNA repair pathways significantly contribute to prostate cancer progression. We hypothesize that overexpression of DNA repair genes may also drive poorer outcomes in prostate cancer. The ribonucleotide reductase small subunit M2 (RRM2) is essential for DNA synthesis and DNA repair by producing dNTPs. It is frequently overexpressed in cancers, but very little is known about its function in prostate cancer.

EXPERIMENTAL DESIGN:

The oncogenic activity of RRM2 in prostate cancer cells was assessed by inhibiting or overexpressing RRM2. The molecular mechanisms of RRM2 function were determined. The clinical significance of RRM2 overexpression was evaluated in 11 prostate cancer clinical cohorts. The efficacy of an RRM2 inhibitor (COH29) was assessed in vitro and in vivo. Finally, the mechanism underlying the transcriptional activation of RRM2 in prostate cancer tissue and cells was determined.

RESULTS:

Knockdown of RRM2 inhibited its oncogenic function, whereas overexpression of RRM2 promoted epithelial mesenchymal transition in prostate cancer cells. The prognostic value of RRM2 RNA levels in prostate cancer was confirmed in 11 clinical cohorts. Integrating the transcriptomic and phosphoproteomic changes induced by RRM2 unraveled multiple oncogenic pathways downstream of RRM2. Targeting RRM2 with COH29 showed excellent efficacy. Thirteen putative RRM2-targeting transcription factors were bioinformatically identified, and FOXM1 was validated to transcriptionally activate RRM2 in prostate cancer.

CONCLUSIONS:

We propose that increased expression of RRM2 is a mechanism driving poor patient outcomes in prostate cancer and that its inhibition may be of significant therapeutic value.

• Authors: Ying Z Mazzu, Joshua Armenia, Goutam Chakraborty, Yuki Yoshikawa, Si'Ana A Coggins, Subhiksha Nandakumar, Travis A Gerke, Mark M Pomerantz, Xintao Qiu, Huiyong Zhao, Mohammad Atiq, Nabeela Khan, Kazumasa Komura, Gwo-Shu Mary Lee, Samson W Fine, Connor Bell, Edward O'Connor, Henry W Long, Matthew L Freedman, Baek Kim, Philip W Kantoff
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 14 Pg. 4480-4492 (07 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30996073 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• FOXM1 protein, human
• Forkhead Box Protein M1
• ribonucleotide reductase M2
• Ribonucleoside Diphosphate Reductase

Topics

• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cells, Cultured
• Cohort Studies
• DNA Repair
• Epithelial-Mesenchymal Transition
• Forkhead Box Protein M1 (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Prognosis
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Ribonucleoside Diphosphate Reductase (genetics, metabolism)
• Survival Rate
• Transcriptional Activation
• Transcriptome
• Xenograft Model Antitumor Assays