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 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.

[1]  A. Zoubeidi,et al.  Targeting Prostate Cancer Subtype 1 by Forkhead Box M1 Pathway Inhibition , 2017, Clinical Cancer Research.

[2]  B. Geiger,et al.  Dual role of E-cadherin in the regulation of invasive collective migration of mammary carcinoma cells , 2017, Scientific Reports.

[3]  F. Saad,et al.  Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  H. Qi,et al.  ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG. , 2016, Biochimica et biophysica acta.

[5]  Hamid Bolouri,et al.  Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer , 2016 .

[6]  Steven J. M. Jones,et al.  The Molecular Taxonomy of Primary Prostate Cancer , 2015, Cell.

[7]  André F. Vieira,et al.  P-cadherin and the journey to cancer metastasis , 2015, Molecular Cancer.

[8]  Henry W. Long,et al.  The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis , 2015, Nature Genetics.

[9]  Jesika S. Faridi,et al.  Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer , 2015, Molecular Cancer Therapeutics.

[10]  Zhi-Hua Zhu,et al.  E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2. , 2015, Biochemical and biophysical research communications.

[11]  Yate-Ching Yuan,et al.  The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro , 2015, Molecular Pharmacology.

[12]  Lawrence D. True,et al.  Integrative Clinical Genomics of Advanced Prostate Cancer , 2015, Cell.

[13]  C. Ponting,et al.  Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer , 2014, BMC Cancer.

[14]  Peter Kraft,et al.  Association of Prostate Cancer Risk Variants with Gene Expression in Normal and Tumor Tissue , 2014, Cancer Epidemiology, Biomarkers & Prevention.

[15]  R. Schinazi,et al.  dNTP pool modulation dynamics by SAMHD1 protein in monocyte-derived macrophages , 2014, Retrovirology.

[16]  Chris Sander,et al.  Copy number alteration burden predicts prostate cancer relapse , 2014, Proceedings of the National Academy of Sciences.

[17]  R. Weiss,et al.  Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies , 2014, Oncogene.

[18]  Mariano J. Alvarez,et al.  Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. , 2014, Cancer cell.

[19]  Soon-Ja Kim,et al.  Dual inhibition by S6K1 and Elf4E is essential for controlling cellular growth and invasion in bladder cancer. , 2014, Urologic oncology.

[20]  Yun Yen,et al.  The prognostic value of ribonucleotide reductase small subunit M2 in predicting recurrence for prostate cancers. , 2014, Urologic oncology.

[21]  Yun Yen,et al.  A small-molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance. , 2013, Cancer research.

[22]  Mark J. Ratain,et al.  Tumour heterogeneity in the clinic , 2013, Nature.

[23]  Demin Li,et al.  A Core Human Primary Tumor Angiogenesis Signature Identifies the Endothelial Orphan Receptor ELTD1 as a Key Regulator of Angiogenesis , 2013, Cancer cell.

[24]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[25]  Manuel A. S. Santos,et al.  P‐cadherin functional role is dependent on E‐cadherin cellular context: a proof of concept using the breast cancer model , 2013, The Journal of pathology.

[26]  A. Sivachenko,et al.  Punctuated Evolution of Prostate Cancer Genomes , 2013, Cell.

[27]  Klemens Vierlinger,et al.  Meta-Analysis of Gene Expression Signatures Defining the Epithelial to Mesenchymal Transition during Cancer Progression , 2012, PloS one.

[28]  Jan Koster,et al.  Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification , 2012, Proceedings of the National Academy of Sciences.

[29]  M. Pagano,et al.  Cyclin F-Mediated Degradation of Ribonucleotide Reductase M2 Controls Genome Integrity and DNA Repair , 2012, Cell.

[30]  R. Gomis,et al.  Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. , 2012, The Journal of clinical investigation.

[31]  F. Markowetz,et al.  The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups , 2012, Nature.

[32]  Benjamin J. Raphael,et al.  The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer , 2016 .

[33]  G. Stein,et al.  A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2 , 2011, Proceedings of the National Academy of Sciences.

[34]  T. Beißbarth,et al.  A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets , 2011, International journal of cancer.

[35]  Eric S. Lander,et al.  The genomic complexity of primary human prostate cancer , 2010, Nature.

[36]  T. Kunkel,et al.  Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools , 2010, Nucleic acids research.

[37]  Peter M Schlag,et al.  Identification of early molecular markers for breast cancer , 2011, Molecular Cancer.

[38]  T. Beißbarth,et al.  Mutated KRAS results in overexpression of DUSP4, a MAP‐kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas , 2010, Genes, chromosomes & cancer.

[39]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[40]  Jing Ma,et al.  Immunohistochemical expression of BRCA1 and lethal prostate cancer. , 2010, Cancer research.

[41]  Jing Chen,et al.  ToppGene Suite for gene list enrichment analysis and candidate gene prioritization , 2009, Nucleic Acids Res..

[42]  Y. Yen,et al.  Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis , 2009, Molecular Cancer.

[43]  R. Bronson,et al.  Broad overexpression of ribonucleotide reductase genes in mice specifically induces lung neoplasms. , 2008, Cancer research.

[44]  Yan Liu,et al.  Risk factors for prostate cancer incidence and progression in the health professionals follow‐up study , 2007, International journal of cancer.

[45]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[47]  W. Gerald,et al.  Gene expression profiling predicts clinical outcome of prostate cancer. , 2004, The Journal of clinical investigation.

[48]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.

[49]  C. Maccalman,et al.  Cadherin switching in ovarian cancer progression , 2003, International journal of cancer.

[50]  A. Chabes,et al.  Controlled Protein Degradation Regulates Ribonucleotide Reductase Activity in Proliferating Mammalian Cells during the Normal Cell Cycle and in Response to DNA Damage and Replication Blocks* , 2000, The Journal of Biological Chemistry.

[51]  Final report on the aspirin component of the ongoing Physicians' Health Study. , 1989, The New England journal of medicine.