Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer Journal Article

   


Authors: Mazzu, Y. Z.; Armenia, J.; Nandakumar, S.; Chakraborty, G.; Yoshikawa, Y.; Jehane, L. E.; Lee, G. S. M.; Atiq, M.; Khan, N.; Schultz, N.; Kantoff, P. W.
Article Title: Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer
Abstract: Although there are molecularly distinct subtypes of prostate cancer, no molecular classification system is used clinically. The ribonucleotide reductase small subunit M2 (RRM2) gene plays an oncogenic role in many cancers. Our previous study elucidated comprehensive molecular mechanisms of RRM2 in prostate cancer (PC). Given the potent functions of RRM2, we set out to determine whether the RRM2 signature can be used to identify aggressive subtypes of PC. We applied gene ontology and pathway analysis in RNA-seq datasets from PC cells overexpressing RRM2. We refined the RRM2 signature by integrating it with two molecular classification systems (PCS and PAM50 subtypes) that define aggressive PC subtypes (PCS1 and luminal B) and correlated signatures with clinical outcomes in six published cohorts comprising 4000 cases of PC. Increased expression of genes in the RRM2 signature was significantly correlated with recurrence, high Gleason score, and lethality of PC. Patients with high RRM2 levels showed higher PCS1 score, suggesting the aggressive PC feature. Consistently, RRM2-regulated genes were highly enriched in the PCS1 signature from multiple PC cohorts. A simplified RRM2 signature (12 genes) was identified by intersecting the RRM2 signature, PCS1 signature, and the PAM50 classifier. Intriguingly, inhibition of RRM2 specifically targets PCS1 and luminal B genes. Furthermore, 11 genes in the RRM2 signature were correlated with enzalutamide resistance by using a single-cell RNA-seq dataset from PC circulating tumor cells. Finally, high expression of RRM2 was associated with an immunosuppressive tumor-immune microenvironment in both primary prostate cancer and metastatic prostate cancer using CIBERSORT analysis and LM22, a validated leukocyte gene signature matrix. These data demonstrate that RRM2 is a driver of aggressive prostate cancer subtypes and contributes to immune escape, suggesting that RRM2 inhibition may be of clinical benefit for patients with PC. © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
Keywords: prostate cancer; pam50; rrm2; molecular subtyping; pcs subtyping
Journal Title: Molecular Oncology
Volume: 14
Issue: 8
ISSN: 1878-0261
Publisher: FEBS Press  
Date Published: 2020-08-01
Start Page: 1881
End Page: 1897
Language: English
DOI: 10.1002/1878-0261.12706
PUBMED: 32385899
PROVIDER: scopus
PMCID: PMC7400792
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85085612516&doi=10.1002%2f1878-0261.12706&partnerID=40&md5=4458b5c3488f373a32f00d6be129d0ce
Notes: Article -- Source: Scopus
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MSK Authors
  1. Goutam Chakraborty
    45 Chakraborty
  2. Nikolaus D Schultz
    486 Schultz
  3. Ying Zhang Mazzu
    34 Mazzu
  4. Philip Wayne Kantoff
    197 Kantoff
  5. Joshua Armenia
    56 Armenia
  6. Nabeela Ali Khan
    15 Khan
  7. Yuki Yoshikawa
    23 Yoshikawa
  8. Mohammad Atiq
    16 Atiq
  9. Subhiksha Nandakumar
    67 Nandakumar
  10. Lina E. Jehane
    14 Jehane
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