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

Chen, Xuanrong ; Augello, Michael A ; Liu, Deli ; Lin, Kevin ; Hakansson, Alex ; Sjöström, Martin LU ; Khani, Francesca ; Deonarine, Lesa D ; Liu, Yang and Travascio-Green, Jaida , et al. (2024) In Nature Communications 15(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Male, Humans, Prostatic Neoplasms/genetics, Receptors, Androgen/metabolism, Response Elements, Gene Expression Regulation, Neoplastic, Prostate/metabolism, Cell Line, Tumor, Androgens/metabolism, Cell Differentiation
in
Nature Communications
volume
15
issue
1
article number
10675
publisher
Nature Publishing Group
external identifiers
  • pmid:39672812
ISSN
2041-1723
DOI
10.1038/s41467-024-53734-z
language
English
LU publication?
no
additional info
© 2024. The Author(s).
id
37bd8c97-9009-4965-a9ed-d1c61e028e83
date added to LUP
2026-02-09 14:20:17
date last changed
2026-02-09 14:20:17
@article{37bd8c97-9009-4965-a9ed-d1c61e028e83,
  abstract     = {{<p>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.</p>}},
  author       = {{Chen, Xuanrong and Augello, Michael A and Liu, Deli and Lin, Kevin and Hakansson, Alex and Sjöström, Martin and Khani, Francesca and Deonarine, Lesa D and Liu, Yang and Travascio-Green, Jaida and Wu, Jiansheng and Chan, Un In and Owiredu, Jude and Loda, Massimo and Feng, Felix Y and Robinson, Brian D and Davicioni, Elai and Sboner, Andrea and Barbieri, Christopher E}},
  issn         = {{2041-1723}},
  keywords     = {{Male; Humans; Prostatic Neoplasms/genetics; Receptors, Androgen/metabolism; Response Elements; Gene Expression Regulation, Neoplastic; Prostate/metabolism; Cell Line, Tumor; Androgens/metabolism; Cell Differentiation}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Canonical androgen response element motifs are tumor suppressive regulatory elements in the prostate}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-53734-z}},
  doi          = {{10.1038/s41467-024-53734-z}},
  volume       = {{15}},
  year         = {{2024}},
}