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Updated: Sep 5, 2025

Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
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LRH-1/NR5A2 interacts with the glucocorticoid receptor to regulate glucocorticoid resistance

Svenja Michalek1,2, Thomas Goj1, Anna Pia Plazzo1

  • 1Department of Biology, Biochemical Pharmacology, University of Konstanz, Konstanz, Germany.

EMBO Reports
|July 8, 2022
PubMed

Insights

Liver Receptor Homolog-1 (LRH-1) directly interacts with the glucocorticoid receptor (GR) in T-cell acute lymphoblastic leukemia (T-ALL). Inhibiting LRH-1 sensitizes T-ALL cells to GR-targeted therapy, even in resistant cases.

Area of Science:

  • Molecular biology
  • Endocrinology
  • Cancer research

Background:

  • Nuclear receptors, including the glucocorticoid receptor (GR), regulate vital physiological and pathological processes.
  • Glucocorticoids (GCs) are crucial for treating T-cell acute lymphoblastic leukemia (T-ALL), but GC resistance leads to poor outcomes.
  • GR activity is modulated by ligand binding and heterodimerization with other transcription factors.

Purpose of the Study:

  • To investigate the interaction between Liver Receptor Homolog-1 (LRH-1) and GR in T-ALL.
  • To determine the functional consequences of LRH-1/GR interaction on T-ALL cell behavior and GC sensitivity.
  • To explore LRH-1 as a therapeutic target for GC-resistant T-ALL.

Main Methods:

  • Co-immunoprecipitation assays to detect direct GR-LRH-1 association.
  • Transcriptional activity assays to assess reciprocal inhibition.
  • Cell proliferation and survival assays in T-ALL cell lines.
  • Assessment of sensitization to GC-induced cell death following LRH-1 interference.

Main Results:

  • A direct, ligand-induced association between LRH-1 and GR was identified in the nucleus.
  • This interaction leads to reciprocal inhibition of their transcriptional activities.
  • Pharmacological or molecular inhibition of LRH-1 significantly impairs T-ALL cell proliferation and survival.
  • Interference with LRH-1 markedly sensitizes T-ALL cells, including GC-resistant ones, to GC-induced cell death.

Conclusions:

  • The direct interaction between GR and LRH-1 is a critical regulator of glucocorticoid sensitivity in T-ALL.
  • Targeting LRH-1 offers a promising strategy to overcome GC resistance in T-ALL.
  • This finding opens new avenues for developing innovative therapies for refractory T-ALL.
Keywords:
NR5A2T cell acute lymphoblastic leukemiaapoptosisglucocorticoid receptorliver receptor homolog-1 (LRH-1)

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