Similar Datasets
Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.
2023-10-24 | PXD043635 | Pride
Project description:Purpose: The glucocorticoid receptor is widely expressed across mutliple tissues, and yet has very tissue specfic actions. This is most likely due to the tissue specific chormatin landscape which dictates GR binding. It identify GR tragets in myeloma as potential therapeutic targets, we have used ChIP-seq to identify myeloma specific GR binding sites. Methods: DNA-chromatin complexes were isolated from MM.1S (GR positive) or MM.1RL (GR negative) cells following a 2 hour treatment with either 1 micromolar dexamethasone or vehicle control. Complexes were immunoprecipitated with either a GR specific antibody or an IgG control and the DNA isolated for next generation sequencing. Results: We identified 8689 high confidence GR binding sites and further correlated those sites to specific genes which are regulated by glucocorticoids through integration with gene expression array data from our lab (submitted to GEO speparately). Conclusions: Overall, our results indentified nearly 400 genes under the direct transcriptional control of glucocorticoids in myeloma cells.
2015-12-22 | GSE63209 | GEO
Project description:Exogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts in solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic. GR is a member of the nuclear receptor family of transcription factors and heavily relies on interactions with coregulator proteins for its transcriptional activity. To elucidate the role of the GR interactome in the altered transcriptional activity of GR following treatment with agonists, antagonists or lead selective GR agonists and modulators (SEGRAMs), we generated comprehensive interactome maps by high-confidence proximity proteomics in lung epithelial carcinoma cells. We found that the GR antagonist RU486 and the SEGRAM Dagrocorat both reduced GR interaction with CREB-binding protein (CBP)/p300 and the mediator complex compared to the full agonist Dexamethasone. Our data offer new insights into the role differential coregulator protein recruitment in shaping specific GR-mediated transcriptional responses.
2024-05-24 | PXD042014 | Pride
Project description:The glucocorticoid receptor (GR) regulates gene expression throughout the human genome in a cell-type-specific manner, governing various aspects of homeostasis. The influence of this transcriptional regulator is seen in multiple pathologies, including cancer. Pharmacological activation of the GR is frequently used to alleviate side-effects caused by therapy for patients with various non-lymphoid solid (i.e. non-hematologic) cancers; however, prior studies have shown that this treatment might also have anti-proliferative action on cancer cells. Nonetheless, the molecular underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the molecular mechanisms of glucocorticoid response in non-lymphoid solid cancers models, focusing on lung cancer. Activation of the GR induces reversible cancer cell dormancy in which cells are tolerant to large array of anti-cancer drugs. This state transition is accompanied by induction of growth factor survival signalling (IGF-1R) and acquired vulnerability to inhibitors of this pathway, both in vitro and in vivo. The observed phenotype is dependent on a single GR target gene - CDKN1C, which encodes for a cell cycle inhibitor protein p57. We have discovered an upstream distal enhancer of CDKN1C, which through GR-induced chromatin looping regulates the expression of this key gene, as confirmed in human tumour specimens. Furthermore, we demonstrate that the SWI/SNF complex composition fine-tunes the GR transcriptional activity at the CDKN1C locus, allowing for precise regulation of cell dormancy induction. Collectively, we show that SWI/SNF-facilitated regulation of CDKN1C underlines GR-induced reversible drug-tolerant state in cancer cells. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anti-cancer therapy related side-effects.
2021-05-17 | PXD021924 | Pride
Project description:Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. In this study, we show that treatment of mice with glucocorticoid eye drops led to a profound regulation of the corneal transcriptome. To determine the global transcriptional profile of GR activity in the cornea, we treated adult wild-type male mice with dexamethasone (a synthetic glucocorticoid) eye drops or vehicle eye drops for 6 hours and then performed RNA sequencing on RNA extracted from whole corneas. All the animals used for this study were adrenalectomized to remove endogenous glucocorticoids. These data demonstrate that a short exposure of glucocorticoids to the cornea results in major changes in the gene expression landscape.
2024-06-27 | GSE213571 | GEO
Project description:Glucocorticoids (GCs) are the most effective anti-inflammatory drugs in current clinical settings, yet their genomic modes of action are poorly understood. GCs bind to the Glucocorticoid Receptor (GR), which acts as a transcription factor to control gene expression in the immune system. Understanding the molecular mechanism that delineates gene repression of pro-inflammatory target genes from gene activation of metabolic genes will help to improve GC therapy and overcome adverse effects.
2021-09-09 | PXD018077 | Pride
Project description:Many stress-related neuropsychiatric disorders display pronounced sex differences in their frequency and clinical symptoms. Glucocorticoids are primary stress hormones that have been implicated in the development of these disorders but whether they contribute to the observed sex bias is poorly understood. Glucocorticoids signal through two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR), that are both expressed at high levels in the hippocampus. To investigate the sex-dependent and independent actions of glucocorticoids in the hippocampus, we developed knockout mice lacking hippocampal GR (GREmx1-cre), MR (MREmx1-cre), or both GR and MR (GRMREmx1-cre). Genome-wide microarrays were performed on RNA isolated from the hippocampus of male and female flox control and knockout mice in order to 1) identify genes dysregulated in a sex-dependent and independent manner by a deficiency in GR, MR, or both GR and MR signaling and 2) identify the genes responsible for the sex-dependent and independent phenotypes observed in these mice.
2023-12-05 | GSE240873 | GEO
Project description:Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. To understand the direct role of GR signaling in the cornea, we developed mice with conditional knockout of GR in the corneal epithelium. Global transcriptomic approaches revealed that loss of GR signaling in the cornea resulted in the dysregulation of a large cohort of genes strongly associated with an enhanced immune response.
2024-06-27 | GSE213660 | GEO
Project description:Various omics datastreams related to mechanisms underlying glucocorticoid receptor action in breast cancer cells - we performed mRNA sequencing and ER/GR-ChIP sequencing.
2023-10-02 | GSE222798 | GEO
Project description:Various omics datastreams related to mechanisms underlying glucocorticoid receptor action in breast cancer cells - we performed mRNA sequencing and ER/GR-ChIP sequencing.
2023-10-02 | GSE222728 | GEO