International Journal of Molecular Medical Science, 2024, Vol.14, No.1, 24-28 http://medscipublisher.com/index.php/ijmms 26 Figure 3 illustrates the complex process of glucocorticoids (GCs) regulating gene expression through their receptors (GR). Under normal circumstances, GR activation can bind to glucocorticoid responsive elements (GREs) on genes, recruit co activators NCOAs and histone acetyltransferases (such as CBP and p300), as well as SWI/SNF complexes, leading to chromatin remodeling. This process promotes the recruitment of BRD4, mediators, and RNA polymerase II pre initiation complexes (PICs), promoting the transcription initiation and extension of downstream target genes. Under inflammatory conditions, NF-κB The p65 subunit of B will bind to its reactive element(κBREs, downstream gene transcription is activated. After GCs treatment, GR (monomers or dimers) recruit NCOR and HDAC proteins by connecting to p65, thereby inhibiting the binding of p-TEFb and recruitment of NELF, leading to transcriptional elongation arrest (B), or chromatin deacetylation by interacting with HDAC proteins, thereby inhibiting BRD4 recruitment, PIC assembly, and transcriptional initiation (C). Figure 4 explores the therapeutic opportunities brought about by the interaction (crosstalk) between glucocorticoid receptors (GR) and other nuclear receptors (NR). In estrogen receptor (ER) positive breast cancer, GR agonist combined with selective ER modulator may improve the treatment response. For triple negative breast cancer (TNBC), GR antagonists may be required, because GR may have a proliferative effect in the absence of ER. In prostate cancer sensitive to the androgen receptor (AR) antagonist enzalutamide (Enz), GR antagonists may prevent GR from replacing AR to regulate gene expression. In the presence of enzalutamide resistance, inhibiting specific co regulatory factors may sensitize prostate cancer cells to enzalutamide. In multiple myeloma (MM), the communication between GR and mineralocorticoid receptor (MR) can be treated by binding GR agonists and MR antagonists. In acute lymphocytic leukemia (ALL), ERRβ Agonists or LRH-1 antagonists may sensitize ALL cells to GR agonist induced cell killing. Finally, the anti-inflammatory activity of GR agonists may be related to PPARα Or PPARγ Enhanced when used in combination with agonists. These therapeutic opportunities reveal that fine-tuning GR and its related nuclear receptor communication can provide new therapeutic strategies. Figure 3 GR complex assembly
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