DPYSL5 is highly expressed in treatment-induced neuroendocrine prostate cancer and promotes lineage plasticity via EZH2/PRC2

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

doi:10.1038/s42003-023-05741-x

Communications Biology (Jan 2024)

DPYSL5 is highly expressed in treatment-induced neuroendocrine prostate cancer and promotes lineage plasticity via EZH2/PRC2

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

Affiliations

Roosa Kaarijärvi: Institute of Biomedicine, University of Eastern Finland
Heidi Kaljunen: Institute of Biomedicine, University of Eastern Finland
Lucia Nappi: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia
Ladan Fazli: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia
Sonia H. Y. Kung: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia
Jaana M. Hartikainen: Institute of Clinical Medicine, Clinical Pathology and Forensic Medicine, University of Eastern Finland
Ville Paakinaho: Institute of Biomedicine, University of Eastern Finland
Janne Capra: Institute of Biomedicine, University of Eastern Finland
Kirsi Rilla: Institute of Biomedicine, University of Eastern Finland
Marjo Malinen: Department of Environmental and Biological Sciences, University of Eastern Finland
Petri I. Mäkinen: A.I. Virtanen Institute, University of Eastern Finland
Seppo Ylä-Herttuala: A.I. Virtanen Institute, University of Eastern Finland
Amina Zoubeidi: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia
Yuzhuo Wang: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia
Martin E. Gleave: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia
Mikko Hiltunen: Institute of Biomedicine, University of Eastern Finland
Kirsi Ketola: Institute of Biomedicine, University of Eastern Finland

DOI: https://doi.org/10.1038/s42003-023-05741-x
Journal volume & issue: Vol. 7, no. 1
pp. 1 – 13

Abstract

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Abstract 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.

Published in Communications Biology

ISSN: 2399-3642 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science: Biology (General)
Website: https://www.nature.com/commsbio/

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