Department of Biology, Biochemical Pharmacology, University of Konstanz, Konstanz, Germany.
Konstanz Research School Chemical Biology KORS-CB, University of Konstanz, Konstanz, Germany.
EMBO Rep. 2022 Sep 5;23(9):e54195. doi: 10.15252/embr.202154195. Epub 2022 Jul 8.
Nuclear receptors are transcription factors with important functions in a variety of physiological and pathological processes. Targeting glucocorticoid receptor (GR) activity using glucocorticoids is a cornerstone in the treatment of patients with T cell acute lymphoblastic leukemia (T-ALL), and resistance to GC-induced cell death is associated with poor outcome and a high risk for relapse. Next to ligand-binding, heterodimerization with other transcription factors presents an important mechanism for the regulation of GR activity. Here, we describe a GC-induced direct association of the Liver Receptor Homolog-1 (LRH-1) with the GR in the nucleus, which results in reciprocal inhibition of transcriptional activity. Pharmacological and molecular interference with LRH-1 impairs proliferation and survival in T-ALL and causes a profound sensitization to GC-induced cell death, even in GC-resistant T-ALL. Our data illustrate that direct interaction between GR and LRH-1 critically regulates glucocorticoid sensitivity in T-ALL opening up new perspectives for developing innovative therapeutic approaches to treat GC-resistant T-ALL.
核受体是转录因子，在多种生理和病理过程中具有重要功能。使用糖皮质激素靶向糖皮质激素受体 (GR) 活性是治疗 T 细胞急性淋巴细胞白血病 (T-ALL) 患者的基石，而对 GC 诱导的细胞死亡的抵抗与不良预后和高复发风险相关。除了配体结合外，与其他转录因子形成异二聚体也是调节 GR 活性的重要机制。在这里，我们描述了 GC 诱导的肝受体同源物-1 (LRH-1) 在核内与 GR 的直接关联，导致转录活性的相互抑制。药理学和分子干扰 LRH-1 可抑制 T-ALL 的增殖和存活，并导致对 GC 诱导的细胞死亡的显著敏感，即使在 GC 耐药的 T-ALL 中也是如此。我们的数据表明，GR 和 LRH-1 之间的直接相互作用在 T-ALL 中对糖皮质激素敏感性具有关键调节作用，为开发治疗 GC 耐药 T-ALL 的创新治疗方法开辟了新的前景。
