In this study, with unbiased integrative informatics analysis and molecular experimental validation, we surprisingly found that cell division cycle 20 (CDC20), denticleless E3 ubiquitin protein ligase (DTL), and ribonucleotide reductase M2 (RRM2), collectively referred to as CDRs, were specifically up-regulated in prostate cancer compared with normal prostate tissues and were further enhanced with prostate cancer progression as well as neuroendocrine prostate cancer (NEPC) lineage plasticity. Here, RRM2 is linked to prostate cancer.