Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer
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 p...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12706 |
| _version_ | 1818337003180130304 |
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| author | Ying Z. Mazzu Joshua Armenia Subhiksha Nandakumar Goutam Chakraborty Yuki Yoshikawa Lina E. Jehane Gwo‐Shu Mary Lee Mohammad Atiq Nabeela Khan Nikolaus Schultz Philip W. Kantoff |
| author_facet | Ying Z. Mazzu Joshua Armenia Subhiksha Nandakumar Goutam Chakraborty Yuki Yoshikawa Lina E. Jehane Gwo‐Shu Mary Lee Mohammad Atiq Nabeela Khan Nikolaus Schultz Philip W. Kantoff |
| author_sort | Ying Z. Mazzu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T14:48:18Z |
| format | Article |
| id | doaj.art-a67bfa99d1ad45d6a66edcca61774047 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-13T14:48:18Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-a67bfa99d1ad45d6a66edcca617740472022-12-21T23:41:25ZengWileyMolecular Oncology1574-78911878-02612020-08-011481881189710.1002/1878-0261.12706Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancerYing Z. Mazzu0Joshua Armenia1Subhiksha Nandakumar2Goutam Chakraborty3Yuki Yoshikawa4Lina E. Jehane5Gwo‐Shu Mary Lee6Mohammad Atiq7Nabeela Khan8Nikolaus Schultz9Philip W. Kantoff10Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USAHuman Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USAHuman Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USADepartment of Medicine Memorial Sloan Kettering Cancer Center New York NY USADepartment of Medicine Memorial Sloan Kettering Cancer Center New York NY USADepartment of Medicine Memorial Sloan Kettering Cancer Center New York NY USADepartment of Medical Oncology Dana‐Farber Cancer Institute Boston MA USADepartment of Medicine Memorial Sloan Kettering Cancer Center New York NY USADepartment of Medicine Memorial Sloan Kettering Cancer Center New York NY USAHuman Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USADepartment of Medicine Memorial Sloan Kettering Cancer Center New York NY USAAlthough 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.https://doi.org/10.1002/1878-0261.12706molecular subtypingPAM50PCS subtypingprostate cancerRRM2 |
| spellingShingle | Ying Z. Mazzu Joshua Armenia Subhiksha Nandakumar Goutam Chakraborty Yuki Yoshikawa Lina E. Jehane Gwo‐Shu Mary Lee Mohammad Atiq Nabeela Khan Nikolaus Schultz Philip W. Kantoff Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer Molecular Oncology molecular subtyping PAM50 PCS subtyping prostate cancer RRM2 |
| title | Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer |
| title_full | Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer |
| title_fullStr | Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer |
| title_full_unstemmed | Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer |
| title_short | Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer |
| title_sort | ribonucleotide reductase small subunit m2 is a master driver of aggressive prostate cancer |
| topic | molecular subtyping PAM50 PCS subtyping prostate cancer RRM2 |
| url | https://doi.org/10.1002/1878-0261.12706 |
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