Canonical androgen response element motifs are tumor suppressive regulatory elements in the prostate

Xuanrong Chen, Michael A. Augello, Deli Liu, Kevin Lin, Alex Hakansson, Martin Sjöström, Francesca Khani, Lesa D. Deonarine, Yang Liu, Jaida Travascio-Green, Jiansheng Wu, Un In Chan, Jude Owiredu, Massimo Loda, Felix Y. Feng, Brian D. Robinson, Elai Davicioni, Andrea Sboner and Christopher E. Barbieri ()
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Xuanrong Chen: Weill Cornell Medicine
Michael A. Augello: Weill Cornell Medicine
Deli Liu: Weill Cornell Medicine
Kevin Lin: Weill Cornell Medicine
Alex Hakansson: Inc.
Martin Sjöström: University of California
Francesca Khani: Weill Cornell Medicine
Lesa D. Deonarine: Weill Cornell Medicine
Yang Liu: Inc.
Jaida Travascio-Green: Weill Cornell Medicine
Jiansheng Wu: Weill Cornell Medicine
Un In Chan: Weill Cornell Medicine
Jude Owiredu: Weill Cornell Medicine
Massimo Loda: Weill Cornell Medicine
Felix Y. Feng: University of California
Brian D. Robinson: Weill Cornell Medicine
Elai Davicioni: Inc.
Andrea Sboner: Weill Cornell Medicine
Christopher E. Barbieri: Weill Cornell Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The androgen receptor (AR) is central in prostate tissue identity and differentiation, and controls normal growth-suppressive, prostate-specific gene expression. It also drives prostate tumorigenesis when hijacked for oncogenic transcription. The execution of growth-suppressive AR transcriptional programs in prostate cancer (PCa) and the potential for reactivation remain unclear. Here, we use a genome-wide approach to modulate canonical androgen response element (ARE) motifs—the classic DNA binding elements for AR—to delineate distinct AR transcriptional programs. We find that activating these AREs promotes differentiation and growth-suppressive transcription, potentially leading to AR+ PCa cell death, while ARE repression is tolerated by PCa cells but deleterious to normal prostate cells. Gene signatures driven by ARE activity correlate with improved prognosis and luminal phenotypes in PCa patients. Canonical AREs maintain a normal, lineage-specific transcriptional program that can be reengaged in PCa cells, offering therapeutic potential and clinical relevance.

Date: 2024
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DOI: 10.1038/s41467-024-53734-z

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