Androgen receptor-mediated assisted loading of the glucocorticoid receptor modulates transcriptional responses in prostate cancer cells [RESEARCH]

Johannes Hiltunen1,3, Laura Helminen1,3, Niina Aaltonen1,3, Kaisa-Mari Launonen1, Hanna Laakso1, Marjo Malinen2, Einari A. Niskanen1, Jorma J. Palvimo1 and Ville Paakinaho1 1Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland; 2Department of Forestry and Environmental Engineering, South-Eastern Finland University of Applied Sciences, FI-45100 Kouvola, Finland

3 These authors contributed equally to this work.

Corresponding author: ville.paakinahouef.fi Abstract

Steroid receptors are involved in a wide array of cross talk mechanisms that regulate diverse biological processes, with significant implications in diseases, particularly in cancers. In prostate cancer, indirect cross talk between androgen receptor (AR) and glucocorticoid receptor NR3C1 (also known as GR) is well documented, wherein AR suppression by antiandrogen therapy leads to elevated GR levels, enabling GR to compensate for and replace AR signaling. However, the existence and impact of direct chromatin cross talk between AR and GR in prostate cancer have remained elusive. Here, our genome-wide investigations reveal that AR activation significantly expands GR chromatin binding. Mechanistically, AR induces remodeling of closed chromatin sites, facilitating GR binding to inaccessible sites. Importantly, coactivation of AR and GR results in distinct transcriptional responses at both the cell population and single-cell levels. Pathways affected by these transcriptional changes are generally associated with improved patient survival. Thus, the direct cross talk between AR and GR yields markedly different outcomes from the known role of GR in circumventing AR blockade by antiandrogens.

Footnotes

[Supplemental material is available for this article.]

Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.280224.124.

Freely available online through the Genome Research Open Access option.

Received November 15, 2024. Accepted May 30, 2025.

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