Canonical AREs are tumor suppressive regulatory elements in the prostate.

TitleCanonical AREs are tumor suppressive regulatory elements in the prostate.
Publication TypeJournal Article
Year of Publication2024
AuthorsAugello MA, Chen X, Liu D, Lin K, Hakansson A, Sjöström M, Khani F, Deonarine LD, Liu Y, Travascio-Green J, Wu J, Loda M, Feng FY, Robinson BD, Davicioni E, Sboner A, Barbieri CE
Date Published2024 Feb 27

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.

Alternate JournalbioRxiv
PubMed ID38464162
PubMed Central IDPMC10925218
Related Faculty: 
Massimo Loda, M.D. Francesca Khani, M.D. Brian Robinson, M.D. Andrea Sboner, Ph.D.

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