DPYSL5 is Highly Expressed in treatment-induced Neuroendocrine Prostate Cancer and Promotes Lineage Plasticity via EZH2/PRC2

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort with 157 patient samples, including 55 t-NEPC patient samples, shows a high expression of DPYSL5 in t-NEPC patients, and that DPYSL5 correlates with neuroendocrine markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces neuron like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 halts proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a novel driver of t-NEPC progression. Gene expression profiling by RNA-seq from LNCaP and C42B cells overexpressing (OE) plvx-CTRL or DPYSL5. Gene expression profiling by RNA-seq from enzalutamide resistant (EnzR) LNCaP and C42B cells treated with non-targeting siRNA or DPYSL5 targeting siRNA. All sequencing was done with Illumina NextSeq 500. UPDATE [May 15, 2025] The treatment time was changed from 48 h to 72 h for Samples GSM4578030-GSM4578032 and GSM5399328-GSM5399331.