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Prognostic and therapeutic significance of COP9 signalosome subunit CSN5 in prostate cancer

Oncogene volume 41, pages 671–682 (2022)Cite this article

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Abstract

Chromosome 8q gain is associated with poor clinical outcomes in prostate cancer, but the underlying biological mechanisms remain to be clarified. CSN5, a putative androgen receptor (AR) partner that is located on chromosome 8q, is the key subunit of the COP9 signalosome, which deactivates ubiquitin ligases. Deregulation of CSN5 could affect diverse cellular functions that contribute to tumor development, but there has been no comprehensive study of its function in prostate cancer. The clinical significance of CSN5 amplification/overexpression was evaluated in 16 prostate cancer clinical cohorts. Its oncogenic activity was assessed by genetic and pharmacologic perturbations of CSN5 activity in prostate cancer cell lines. The molecular mechanisms of CSN5 function were assessed, as was the efficacy of the CSN5 inhibitor CSN5i-3 in vitro and in vivo. Finally, the transcription cofactor activity of CSN5 in prostate cancer cells was determined. The prognostic significance of CSN5 amplification and overexpression in prostate cancer was independent of MYC amplification. Inhibition of CSN5 inhibited its oncogenic function by targeting AR signaling, DNA repair, multiple oncogenic pathways, and spliceosome regulation. Furthermore, inhibition of CSN5 repressed metabolic pathways, including oxidative phosphorylation and glycolysis in AR-negative prostate cancer cells. Targeting CSN5 with CSN5i-3 showed potent antitumor activity in vitro and in vivo. Importantly, CSN5i-3 synergizes with PARP inhibitors to inhibit prostate cancer cell growth. CSN5 functions as a transcription cofactor to cooperate with multiple transcription factors in prostate cancer. Inhibiting CSN5 strongly attenuates prostate cancer progression and could enhance PARP inhibition efficacy in the treatment of prostate cancer.

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Fig. 1: Amplification of CSN5 is correlated with poor clinical outcomes in prostate cancer.
Fig. 2: Overexpression of CSN5 is correlated with poor clinical outcomes in prostate cancer.
Fig. 3: The oncogenic roles of CSN5 in AR-positive prostate cancer.
Fig. 4: Inhibition of CSN5 repressed oncogenic activity of CSN5 in AR negative prostate cancer cells.
Fig. 5: CSN5i-3 inhibited oncogenic activity of CSN5 in prostate cancer cells.
Fig. 6: CSN5i-3 synergized with PARPi and strongly inhibited xenograft tumor growth.

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Acknowledgements

This research was funded by a Department of Defense Prostate Cancer Research Program Translational Science Award (W81XWH-20-1-0114 to P.W. Kantoff) and in part through the NIH/NCI Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748). We acknowledge that Eva Altmann from Novartis Institutes for BioMedical Research (Switzerland) kindly provided CSN5i-3 for the study; Lorelei A. Mucci from the Department of Epidemiology, Harvard T.H. Chan School of Public Health (Boston, Massachusetts) kindly provided information on the PHS/HPFS cohorts. We thank Margaret McPartland for editing and members of the Kantoff laboratory for help and discussion. This research was funded by a Department of Defense Prostate Cancer Research Program Translational Science Award (W81XWH-20-1-0114 to P.W. Kantoff) and in part through the NIH/NCI Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748).

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Authors and Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Ying Z. Mazzu, Yu-Rou Liao, Lina E. Jehane, Sai Harisha Rajanala, Goutam Chakraborty, Yu Chen & Philip W. Kantoff

  2. Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Subhiksha Nandakumar

  3. Epigenetics Innovation Lab, Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Richard P. Koche & Ruifang Li

  4. Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    HuiYong Zhao

  5. Moffitt Cancer Center, Tampa, FL, USA

    Travis A. Gerke

  6. Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA

    Gwo-Shu Mary Lee

  7. Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Gouri J. Nanjangud

  8. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Anuradha Gopalan

  9. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Yu Chen

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Contributions

Conception and design: YZM and PWK. Development of methodology: YZM, YL, RPK, RL, GJN and YC. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): YZM, YL, LEJ, SN, RPK, SHR, RL, HZ, TAG and GC. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): YZM, YL, SN and RPK. Writing, review and/or revision of the paper: YZM, YL, RPK, YC and PWK. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): YZM, TAG, GL, AG, YC and PWK. Study supervision: YZM and PWK.

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Correspondence to Ying Z. Mazzu or Philip W. Kantoff.

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Competing interests

As of August 5, 2021, P.W. Kantoff reports the following disclosures for the last 24-month period: he has investment interest in Cogent Biosciences, Context Therapeutics LLC, DRGT, Mirati, Placon, PrognomIQ, Seer Biosciences, SnyDevRx and XLink; he is a company board member for Context Therapeutics LLC; he is a company founder for XLink; he is co-founder and CEO of Convergent Therapeutics, he is/was a consultant/scientific advisory board member for Anji, Bavarian Nordic Immunotherapeutics, Candel, DRGT, Immunis, AI (previously OncoCellMDX), Janssen, Progenity, PrognomIQ, Seer Biosciences, SynDevRX, Tarveda Therapeutics, and Veru, and serves on data safety monitoring boards for Genentech/Roche and Merck. He reports spousal association with Bayer.

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Mazzu, Y.Z., Liao, YR., Nandakumar, S. et al. Prognostic and therapeutic significance of COP9 signalosome subunit CSN5 in prostate cancer. Oncogene 41, 671–682 (2022). https://doi.org/10.1038/s41388-021-02118-4

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