Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.

Abstract

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.

SIGNIFICANCE:

Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.

• Authors: Simon Linder, Marlous Hoogstraat, Suzan Stelloo, Nils Eickhoff, Karianne Schuurman, Hilda de Barros, Maartje Alkemade, Elise M Bekers, Tesa M Severson, Joyce Sanders, Chia-Chi Flora Huang, Tunc Morova, Umut Berkay Altintas, Liesbeth Hoekman, Yongsoo Kim, Sylvan C Baca, Martin Sjöström, Anniek Zaalberg, Dorine C Hintzen, Jeroen de Jong, Roelof J C Kluin, Iris de Rink, Claudia Giambartolomei, Ji-Heui Seo, Bogdan Pasaniuc, Maarten Altelaar, René H Medema, Felix Y Feng, Amina Zoubeidi, Matthew L Freedman, Lodewyk F A Wessels, Lisa M Butler, Nathan A Lack, Henk van der Poel, Andries M Bergman, Wilbert Zwart
• Journal: Cancer discovery (Cancer Discov) Vol. 12 Issue 9 Pg. 2074-2097 (09 02 2022) ISSN: 2159-8290 [Electronic] United States
• PMID: 35754340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• ARNTL Transcription Factors
• Androgens
• Nitriles
• Receptors, Androgen

Topics

• ARNTL Transcription Factors (genetics)
• Androgens (pharmacology, therapeutic use)
• Cell Line, Tumor
• Circadian Rhythm
• Drug Resistance, Neoplasm (genetics)
• Epigenomics
• Humans
• Male
• Nitriles (therapeutic use)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Receptors, Androgen (genetics)