PROSTATE cancer (PCa) is intricately tied to the androgen receptor (AR), a transcription factor vital for the development and maintenance of prostate tissue. While AR orchestrates growth-suppressive gene expression in normal prostate cells, its reprogramming in PCa hijacks its function to drive oncogenic transcription. This duality highlights AR as both a key driver of prostate tumorigenesis and a critical therapeutic target, even in advanced, treatment-resistant cases.
In PCa, AR’s oncogenic reprogramming involves epigenetic changes that alter its cistrome – its genome-wide binding sites – towards enhancers enriched with motifs for transcription factors like FOXA1 and HOXB13. These shifts diminish AR’s growth-suppressive roles while enhancing proliferation and invasion. However, less understood are the lost functions of AR during tumor progression, particularly its regulation through canonical Androgen Response Elements (AREs).
Recent research has unveiled the crucial role of AREs in governing AR’s growth-suppressive transcriptional programs. These elements, essential for normal prostate differentiation, appear depleted in cancer-associated AR cistromes. By modulating ARE-containing regulatory regions genome-wide, researchers have reengaged growth-suppressive AR functions in PCa cells, offering therapeutic potential.
Histone deacetylase 3 (HDAC3) emerges as a key player, binding ARE-enriched chromatin to facilitate AR’s growth-suppressive effects. This highlights HDAC3 as a promising therapeutic target and emphasises the importance of chromatin context in AR-dependent transcription.
Clinically, this research has significant implications. The transcriptional signatures associated with ARE-mediated AR activity correlate with patient prognosis, opening doors for biomarker discovery. Furthermore, strategies like bipolar androgen therapy and supraphysiologic testosterone, which cyclically activate AR, may leverage these growth-suppressive pathways, offering innovative treatment options for advanced PCa.
By elucidating AR’s context-dependent functions, this study advances our understanding of its dual role in PCa and underscores the therapeutic potential of targeting AR’s growth-suppressive mechanisms. This progress marks a step forward in refining treatment strategies and improving patient outcomes in prostate cancer.
Katie Wright, EMJ
Reference
Chen X et al. Canonical androgen response element motifs are tumor suppressive regulatory elements in the prostate. Nat Commun. 2024;15(1):10675.
