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 the neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort, comprising 135 patient tumor samples, including 55 t-NEPC patient samples, exhibits a high expression of DPYSL5 in t-NEPC patient tumors. DPYSL5 correlates with neuroendocrine-related markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces a 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 decreases 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 driver of t-NEPC progression.
Communications biology. 2024 Jan 18*** epublish ***
Roosa Kaarijärvi, Heidi Kaljunen, Lucia Nappi, Ladan Fazli, Sonia H Y Kung, Jaana M Hartikainen, Ville Paakinaho, Janne Capra, Kirsi Rilla, Marjo Malinen, Petri I Mäkinen, Seppo Ylä-Herttuala, Amina Zoubeidi, Yuzhuo Wang, Martin E Gleave, Mikko Hiltunen, Kirsi Ketola
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Institute of Clinical Medicine, Clinical Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland., Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland., A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland., Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. .