Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer
Year: 2025
Type: article
Abstract: Androgen receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase 2 clinical trial, we epigenetically profile enhancer/promoter activities with acetylation of lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identify a distinct subset of H3K27ac-differentially marked regions that are associated with treatment responsiveness, which we successfully validate in mCRPC patient-derived xenograft (PDX) models. In silico analyses reveal histone deacetylase (HDAC)3 to critically drive resistance to hormonal interventions, which we validate in vitro. Critically, we identify the pan-HDAC inhibitor vorinostat to be effective in decreasing tumor cell proliferation, both in vitro and in vivo. Moreover, we uncover evidence for HDAC3 working together with glucocorticoid receptor (GR) as a potential mechanism for this therapeutic effect. These findings demonstrate the rationale for therapeutic strategies including HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.
Source: Cell Reports Medicine
Authors: Tesa M. Severson, Emma Minnee, Yanyun Zhu, Karianne Schuurman, Holly M. Nguyen, Lisha G. Brown, Sini Hakkola, Renee Menezes, Sebastian Gregoricchio, Yongsoo Kim, Jeroen Kneppers, Simon Linder, Suzan Stelloo, Cor Lieftink, Michiel S. van der Heijden, Matti Nykter, Vincent van der Noort, Joyce Sanders, Ben Morris, Guido Jenster, Geert JLH van Leenders, Mark Pomerantz, Matthew L. Freedman, Roderick L. Beijersbergen, Alfonso Urbanucci, Lodewyk Wessels, Peter S. Nelson, Eva Corey, Stefan Prekovic, Wilbert Zwart, Andries M. Bergman
Institutions: The Netherlands Cancer Institute, Oncode Institute, University of Washington, Tampere University, University of Tampere, Erasmus MC, Erasmus MC Cancer Institute, Harvard University, Dana-Farber Cancer Institute, Broad Institute, Oslo University Hospital, Delft University of Technology, Fred Hutch Cancer Center, Eindhoven University of Technology, Amsterdam University Medical Centers, University of Amsterdam
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: U.S. Department of Defense, Prostate Cancer Foundation, Kreftforeningen, Finnish Cancer Institute, Academy of Finland, Ministerie van Volksgezondheid, Welzijn en Sport, KWF Kankerbestrijding, Astellas Pharma, Astellas Pharma Europe, Sigrid Juséliuksen Säätiö, Syöpäsäätiö, Oncode Institute, Astellas Pharma, Netherlands, National Cancer Institute
OpenAlex ID: W4411958981