AR is a tissue-specific transcription factor essential for normal prostate development. It functions through androgen response elements (AREs) - DNA motifs recognized by the AR - to regulate gene expression. In prostate cancer, AR is co-opted from its role in activating differentiation-associated genes to drive oncogenic transcriptional networks, moving away from AREs toward other DNA motifs.
To investigate these changes, a functional genomic strategy called Modifiers of ARE-Containing Chromatin (MACC) was developed to interrogate the consequences of turning on or off AREs, and the genes controlled by them, directly. MACCs are artificial transcription factors that target AREs by combining the AR DNA-binding domain with various chromatin-modifying modules, allowing precise remodeling of AR-bound enhancer regions.
Using these constructs revealed that activating AREs inhibits the growth of human prostate cancer cells, by inducing apoptosis and reinstating normal-like cellular functions. In contrast, repressing AREs promotes cancerous behavior by enhancing cell cycle progression. By systematically altering these AR-bound enhancers, MACCs offer a valuable method to dissect how AR transitions from growth-regulating to cancer-promoting states. These unique insights into the distinct transcriptional programs controlled by AR now can allow researchers to determine how to attack the switches that toggle between them to find new targets to suppress prostate cancer growth.
This mechanism is particularly critical in the advanced stages of prostate cancer, emphasizing the importance of understanding these regulatory changes. Gaining insight into these transitions is essential for elucidating prostate cancer development and for designing strategies to prevent or reverse disease progression.
The principles behind MACCs could also be adapted to other cancers, such as breast and lung cancer, where other lineage-specific master transcription factors have multiple functions and undergo reprogramming, thereby posing challenges for targeted therapy.
Figure Legend: Schematic shows MACC constructs to modulate ARE activity upon Tamoxifen treatment.
Written by: Xuanrong Chen1,2 and Christopher E. Barbieri1,2,3
- Department of Urology, Weill Cornell Medicine, New York, NY
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY