Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence
| Autor: | Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M., Severson, Tesa M., Sanders, Joyce, Huang, Chia Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C., Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C., de Jong, Jeroen, Kluin, Roelof J.C., de Rink, Iris, Giambartolomei, Claudia, Seo, Ji Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H., Feng, Felix Y., Zoubeidi, Amina, Freedman, Matthew L., Wessels, Lodewyk F.A., Butler, Lisa M., Lack, Nathan A., van der Poel, Henk, Bergman, Andries M., Zwart, Wilbert, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics |
|---|---|
| Přispěvatelé: | Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Chemical Biology, Pathology, CCA - Cancer biology and immunology, Ethics, Law & Medical humanities, APH - Quality of Care, Urology |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Urologic Diseases
Epigenomics Male Aging Oncology and Carcinogenesis ARNTL Transcription Factors/genetics Drug Resistance Drug Resistance Neoplasm/genetics SDG 3 – Goede gezondheid en welzijn Castration-Resistant Article Cell Line Androgen SDG 3 - Good Health and Well-being Cell Line Tumor Receptors Nitriles Phenylthiohydantoin Taverne 2.1 Biological and endogenous factors Humans Aetiology Androgens/pharmacology Cancer Prostatic Neoplasms Castration-Resistant/drug therapy Castration-Resistant/drug therapy Tumor Nitriles/therapeutic use Neoplasm/genetics Prostate Cancer Aryl Hydrocarbon Receptor Nuclear Translocator Androgen/genetics Prostatic Neoplasms ARNTL Transcription Factors Receptors Androgen/genetics Circadian Rhythm Prostatic Neoplasms Castration-Resistant Oncology 5.1 Pharmaceuticals Drug Resistance Neoplasm Receptors Androgen Benzamides Androgens Neoplasm Development of treatments and therapeutic interventions Biotechnology |
| Zdroj: | Cancer Discovery, 12(9), 2074-2097. American Association for Cancer Research Inc. Cancer Discovery, 12(9), 2074. American Association for Cancer Research Inc. Linder, S, Hoogstraat, M, Stelloo, S, Eickhoff, N, Schuurman, K, de Barros, H, Alkemade, M, Bekers, E M, Severson, T M, Sanders, J, Huang, C-C F, Morova, T, Altintas, U B, Hoekman, L, Kim, Y, Baca, S C, Sjöström, M, Zaalberg, A, Hintzen, D C, de Jong, J, Kluin, R J C, de Rink, I, Giambartolomei, C, Seo, J-H, Pasaniuc, B, Altelaar, M, Medema, R H, Feng, F Y, Zoubeidi, A, Freedman, M L, Wessels, L F A, Butler, L M, Lack, N A, van der Poel, H, Bergman, A M & Zwart, W 2022, ' Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence ', Cancer discovery, vol. 12, no. 9, pp. 2074-2097 . https://doi.org/10.1158/2159-8290.CD-21-0576 Cancer Discov Cancer discovery, 12(9) Cancer discovery, vol 12, iss 9 Cancer discovery, 12(9), 2074-2097. American Association for Cancer Research Inc. |
| ISSN: | 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-21-0576 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|