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LRH-1/NR5A2 interacts with the glucocorticoid receptor to regulate glucocorticoid resistance


Michalek, Svenja; Goj, Thomas; Plazzo, Anna Pia; Marovca, Blerim; Bornhauser, Beat; Brunner, Thomas (2022). LRH-1/NR5A2 interacts with the glucocorticoid receptor to regulate glucocorticoid resistance. EMBO Reports, 23(9):e54195.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Life Sciences > Genetics
Language:English
Date:5 September 2022
Deposited On:15 Dec 2022 10:20
Last Modified:28 May 2024 01:43
Publisher:Nature Publishing Group
ISSN:1469-221X
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.15252/embr.202154195
PubMed ID:35801407
  • Content: Published Version
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)