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.