Hiltunen Johannes, Helminen Laura, Aaltonen Niina, Launonen Kaisa-Mari, Laakso Hanna, Malinen Marjo, Niskanen Einari A, Palvimo Jorma J, Paakinaho Ville
Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
Department of Forestry and Environmental Engineering, South-Eastern Finland University of Applied Sciences, FI-45100 Kouvola, Finland.
Genome Res. 2025 Aug 1;35(8):1717-1732. doi: 10.1101/gr.280224.124.
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.
类固醇受体参与了一系列广泛的相互作用机制，这些机制调节着多种生物过程，对疾病尤其是癌症具有重要影响。在前列腺癌中，雄激素受体（AR）与糖皮质激素受体NR3C1（也称为GR）之间的间接相互作用已有充分记录，其中抗雄激素治疗对AR的抑制会导致GR水平升高，使GR能够补偿并取代AR信号传导。然而，前列腺癌中AR与GR之间直接的染色质相互作用的存在及其影响仍不清楚。在此，我们的全基因组研究表明，AR激活显著扩展了GR在染色质上的结合。从机制上讲，AR诱导封闭染色质位点的重塑，促进GR与难以接近的位点结合。重要的是，AR和GR的共同激活在细胞群体和单细胞水平上都导致了不同的转录反应。受这些转录变化影响的通路通常与患者生存率提高相关。因此，AR与GR之间的直接相互作用产生的结果与GR在通过抗雄激素规避AR阻断中的已知作用明显不同。
