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

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.

NR5A2 gene affects the overall survival of LUAD patients by regulating the activity of CSCs through SNP pathway by OCLR algorithm and immune score

“…By comparing the structure of the NR5A gene in different organisms, it was found that the structure of the NR5A2 gene in various organisms is conserved, and there is obvious gene duplication in the evolutionary process, indicating that the NR5A2 gene is not prone to mutations and has high specificity in the expression of lung CSCs [ 56 ]. Furthermore, the variable shear location of the mutation site is associated with survival prognosis and the degree of drug resistance in patients with LUAD, which will be conducive to the drug guidance of second-line therapy and locating drug-resistant mutation gene sites, and will greatly improve the survival time of patients [ [57] , [58] , [59] , [60] , [61] ].…”

NR5A2 as a potential target for exercise to improve metabolic syndrome

“…NR5A2 expression is downregulated in metabolic syndrome [26]. Relevant literature reports that NR5A2 interacts with glucocorticoid receptors to regulate glucocorticoid resistance [23,27]. Therefore, NR5A2 might affect metabolic syndrome.…”

Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy

“…GCs, hormones synthesized by the adrenal glands, are released into the bloodstream to maintain homeostasis and regulate the body's response to various stressors [ 95 , 96 ]. These hormones exert their effects through interaction with the GC receptor (GR), which is ubiquitously expressed across various cell types, thereby influencing a broad spectrum of pathophysiological pathways with pronounced impacts on metabolism and immunity [ 97 ]. The suppressive effect of GCs on T cell functionality is well established [ 98 , 99 ].…”