Androgen receptor (AR) signaling plays a critical role in prostate cancer progression and remains a primary therapeutic target. Despite the efficacy of androgen deprivation therapy (ADT), most patients eventually develop castration-resistant prostate cancer (CRPC), characterized by the reactivation of AR signaling through various mechanisms. While the role of AR as a transcriptional activator is well-documented, emerging research indicates that it also functions as a transrepressor for specific targets.

Liver receptor homolog-1 (LRH-1, encoded by NR5A2), a nuclear receptor involved in metabolism and steroidogenesis, has been previously implicated in promoting progression and intratumoral steroidogenesis in CRPC; however, its reciprocal regulation by AR signaling remains elusive.

A recent study published in Genes & Diseases by researchers from The Chinese University of Hong Kong, Southern Medical University, and Sun Yat-sen University reveals a complex, androgen-driven feedback loop where AR directly functions as a transcriptional repressor of the LRH-1 gene through specialized chromatin architecture.

Expression profiling across clinical datasets and experimental models demonstrated that LRH-1 is significantly upregulated in CRPC and in response to androgen deprivation, whereas AR activity exhibits an inverse relationship with LRH-1 expression. Gene set enrichment and correlation analyses further revealed that tumors with elevated LRH-1 expression display reduced androgen-responsive gene signatures, supporting a negative regulatory axis between AR signaling and LRH-1 levels. These findings suggest that LRH-1 contributes to disease progression, particularly under conditions of diminished androgen signaling.

Using a combination of ChIP-seq, Hi-C, and 3C data analysis, researchers found that AR occupies a specific distal enhancer region approximately 140 kb downstream of the NR5A2 transcription start site. In the presence of androgens, AR facilitates the formation of a long-range chromatin loop that brings this distal enhancer into physical contact with the NR5A2 promoter. This looping conformation enables AR to recruit corepressors—such as ERG, EZH2, and histone deacetylases (HDACs)—to the regulatory regions of NR5A2, effectively silencing LRH-1 transcription.

These epigenetic modifications lead to a reduction in active histone marks, such as H3K4me3, and an increase in paused RNA polymerase II peaks in the promoter and enhancer regions, further supporting the suppression effect of androgen-activated AR on the RNA pol II-mediated mRNA synthesis of NR5A2. Conversely, androgen withdrawal during ADT dissipates these inhibitory loops, leading to the significant overexpression of LRH-1.

In conclusion, this work establishes AR as a direct transcriptional repressor of LRH-1 through androgen-driven chromatin looping, revealing a previously unknown mechanism of gene regulation in prostate cancer. These findings underscore the significance of the AR–LRH-1 interplay in disease progression and suggest that targeting this regulatory axis may offer novel therapeutic opportunities for managing advanced and castration-resistant prostate cancer.

Reference

Title of the original paper: Androgen receptor acts as the transcriptional repressor of the nuclear receptor LRH-1 via the androgen-driven chromatin looping conformation in prostate cancer.

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101903

Funding Information:
National Natural Science Foundation of China (No. 81802575, 82072830, 81974457, 81872283)
Science and Technology Project of Shenzhen (No. JCYJ20210324130607021)
Natural Science Foundation of Guangdong Province, China (No. 2019A1515012079)
Health and Medical Research Fund (No. 02130066)
Food and Health Bureau of Hong Kong
General Research Fund (No. 14107623)
Research Grants Council of Hong Kong

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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