Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer
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.
Authors
- Holly M. Nguyen (ORCID: https://orcid.org/0000-0002-6331-8089)
- Wilbert Zwart (ORCID: https://orcid.org/0000-0002-9823-7289)
- Karianne Schuurman (ORCID: https://orcid.org/0000-0002-9278-0571)
- Sebastian Gregoricchio (ORCID: https://orcid.org/0000-0001-9209-5403)
- Tesa Severson (ORCID: https://orcid.org/0000-0002-7568-4705)
- Mark M. Pomerantz
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Lodewyk F.A. Wessels (ORCID: https://orcid.org/0000-0002-1656-6995)
- Geert JLH van Leenders
- Yongsoo Kim (ORCID: https://orcid.org/0000-0002-4277-0279)
- Emma Minnee
- Alfonso Urbanucci (ORCID: https://orcid.org/0000-0003-2931-3652)
- Suzan Stelloo (ORCID: https://orcid.org/0000-0002-6696-836X)
- Andries M. Bergman (ORCID: https://orcid.org/0000-0001-5223-2549)
- Michiel S. van der Heijden (ORCID: https://orcid.org/0000-0002-4407-7881)
- Joyce Sanders (ORCID: https://orcid.org/0000-0002-0551-7813)
- Guido Jenster (ORCID: https://orcid.org/0000-0002-8658-2552)
- Vincent van der Noort (ORCID: https://orcid.org/0000-0002-4910-4535)
- Ben Morris (ORCID: https://orcid.org/0000-0002-9850-6071)
- Renée X. de Menezes (ORCID: https://orcid.org/0000-0002-1378-2721)
- Jeroen Kneppers (ORCID: https://orcid.org/0000-0002-6548-2480)
- Roderick L. Beijersbergen (ORCID: https://orcid.org/0000-0003-0116-4130)
- Simon Linder (ORCID: https://orcid.org/0000-0002-3315-305X)
- Matti Nykter (ORCID: https://orcid.org/0000-0001-6956-2843)
- Sini Hakkola
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- Stefan Preković (ORCID: https://orcid.org/0000-0002-7051-9321)
- Yanyun Zhu (ORCID: https://orcid.org/0000-0002-4954-4864)
- Cor Lieftink (ORCID: https://orcid.org/0000-0002-2754-4150)
- Matthew L. Freedman (ORCID: https://orcid.org/0000-0002-0151-1238)
- Lisha G. Brown (ORCID: https://orcid.org/0009-0009-7262-2080)
Institutions
- Harvard University (US)
- Tampere University of Applied Sciences (FI)
- University of Washington (US)
- Dutch Cancer Society (NL)
- Fred Hutch Cancer Center (US)
- Oncode Institute (NL)
- Dana-Farber Cancer Institute (US)
- Cancer Genomics Centre (NL)
- Cancer Registry of Norway (NO)
- Erasmus MC Cancer Institute (NL)
- Erasmus University Rotterdam (NL)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102215
- Citations
- 4
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 6.07
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- Academy of Finland
- Ministerie van Volksgezondheid, Welzijn en Sport
- KWF Kankerbestrijding
- Astellas Pharma
- Astellas Pharma Europe
- Oncode Institute
- Astellas Pharma, Netherlands