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Canonical AREs are tumor suppressive regulatory elements in the prostate

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

The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive prostate-specific gene expression 1 . It is also a key driver of prostate tumorigenesis, becoming "hijacked" to drive oncogenic transcription 2-5 . However, the regulatory elements determining the execution of the growth suppressive AR transcriptional program, and whether this can be reactivated in prostate cancer (PCa) cells remains unclear. Canonical androgen response element (ARE) motifs are the classic DNA binding element for AR 6 . Here, we used a genome-wide strategy to modulate regulatory elements containing AREs to define distinct AR transcriptional programs. We find that activation of... (More)

The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive prostate-specific gene expression 1 . It is also a key driver of prostate tumorigenesis, becoming "hijacked" to drive oncogenic transcription 2-5 . However, the regulatory elements determining the execution of the growth suppressive AR transcriptional program, and whether this can be reactivated in prostate cancer (PCa) cells remains unclear. Canonical androgen response element (ARE) motifs are the classic DNA binding element for AR 6 . Here, we used a genome-wide strategy to modulate regulatory elements containing AREs to define distinct AR transcriptional programs. We find that activation of these AREs is specifically associated with differentiation and growth suppressive transcription, and this can be reactivated to cause death in AR + PCa cells. In contrast, repression of AREs is well tolerated by PCa cells, but deleterious to normal prostate cells. Finally, gene expression signatures driven by ARE activity are associated with improved prognosis and luminal phenotypes in human PCa patients. This study demonstrates that canonical AREs are responsible for a normal, growth-suppressive, lineage-specific transcriptional program, that this can be reengaged in PCa cells for potential therapeutic benefit, and genes controlled by this mechanism are clinically relevant in human PCa patients.

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publishing date
type
Working paper/Preprint
publication status
published
subject
publisher
bioRxiv
external identifiers
  • pmid:38464162
DOI
10.1101/2024.02.23.581466
language
English
LU publication?
no
id
18dcbc3b-f47f-4163-b423-227dd6a47de2
date added to LUP
2026-02-18 09:04:31
date last changed
2026-02-18 09:06:09
@misc{18dcbc3b-f47f-4163-b423-227dd6a47de2,
  abstract     = {{<p>The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive prostate-specific gene expression 1 . It is also a key driver of prostate tumorigenesis, becoming "hijacked" to drive oncogenic transcription 2-5 . However, the regulatory elements determining the execution of the growth suppressive AR transcriptional program, and whether this can be reactivated in prostate cancer (PCa) cells remains unclear. Canonical androgen response element (ARE) motifs are the classic DNA binding element for AR 6 . Here, we used a genome-wide strategy to modulate regulatory elements containing AREs to define distinct AR transcriptional programs. We find that activation of these AREs is specifically associated with differentiation and growth suppressive transcription, and this can be reactivated to cause death in AR + PCa cells. In contrast, repression of AREs is well tolerated by PCa cells, but deleterious to normal prostate cells. Finally, gene expression signatures driven by ARE activity are associated with improved prognosis and luminal phenotypes in human PCa patients. This study demonstrates that canonical AREs are responsible for a normal, growth-suppressive, lineage-specific transcriptional program, that this can be reengaged in PCa cells for potential therapeutic benefit, and genes controlled by this mechanism are clinically relevant in human PCa patients.</p>}},
  author       = {{Augello, Michael A and Chen, Xuanrong 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 Loda, Massimo and Feng, Felix Y and Robinson, Brian D and Davicioni, Elai and Sboner, Andrea and Barbieri, Christopher E}},
  language     = {{eng}},
  month        = {{02}},
  note         = {{Preprint}},
  publisher    = {{bioRxiv}},
  title        = {{Canonical AREs are tumor suppressive regulatory elements in the prostate}},
  url          = {{http://dx.doi.org/10.1101/2024.02.23.581466}},
  doi          = {{10.1101/2024.02.23.581466}},
  year         = {{2024}},
}