Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity

• Published in: Cell reports (Cambridge) Vol. 36; no. 10; p. 109625
• Main Authors: Grbesa, Ivana, Augello, Michael A., Liu, Deli, McNally, Dylan R., Gaffney, Christopher D., Huang, Dennis, Lin, Kevin, Ivenitsky, Daria, Goueli, Ramy, Robinson, Brian D., Khani, Francesca, Deonarine, Lesa D., Blattner, Mirjam, Elemento, Olivier, Davicioni, Elai, Sboner, Andrea, Barbieri, Christopher E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.09.2021
• Subjects: Androgens - immunology; Animals; Carcinogenesis - genetics; Chromatin - metabolism; Gene Expression Regulation, Neoplastic - genetics; Male; Mice, Transgenic; Prostate - metabolism; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Receptors, Androgen - metabolism; Repressor Proteins - metabolism; Signal Transduction - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109625

The normal androgen receptor (AR) cistrome and transcriptional program are fundamentally altered in prostate cancer (PCa). Here, we profile the chromatin landscape and AR-directed transcriptional program in normal prostate cells and show the impact of SPOP mutations, an early event in prostate tumorigenesis. In genetically normal mouse prostate organoids, SPOP mutation results in accessibility and AR binding patterns similar to that of human PCa. Consistent with dependence on AR signaling, castration of SPOP mutant mouse models results in the loss of neoplastic phenotypes, and human SPOP mutant PCa shows a favorable response to AR-targeted therapies. Together, these data validate mouse prostate organoids as a robust model for studying epigenomic and transcriptional alterations in normal prostate, provide valuable datasets for further studies, and show that a single genomic alteration may be sufficient to reprogram the chromatin of normal prostate cells toward oncogenic phenotypes, with potential therapeutic implications for AR-targeting therapies. [Display omitted] •Epigenomic and transcriptional response to androgen in normal prostate organoids•AR cistrome and chromatin landscape reprogrammed in SPOP mutant prostate organoids•In vivo models of SPOP mutant prostate cancer respond to modulation of AR signaling•SPOP mutation is associated with improved response to anti-AR therapies Grbesa et al. use multilevel epigenomic and transcriptional profiling to characterize genetically normal prostate organoids and show the impact of an early cancer driver (SPOP mutation). Integrative analysis identifies transcriptional programs that are AR regulated and reprogrammed by SPOP mutation, suggesting a basis for enhanced sensitivity to AR-targeting therapies.