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

Ivana Grbesa, Michael A. Augello, Deli Liu, Dylan R. McNally, Christopher D. Gaffney, Dennis Huang, Kevin Lin, Daria Ivenitsky, Ramy Goueli, Brian D. Robinson, Francesca Khani, Lesa D. Deonarine, Mirjam Blattner, Olivier Elemento, Elai Davicioni, Andrea Sboner, Christopher E. Barbieri

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number109625
JournalCell Reports
Volume36
Issue number10
DOIs
StatePublished - Sep 7 2021
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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