Hypoxia- And Dexamethasone-Dependent Hif1 Alpha-Glucocorticoid Receptor Interaction Leads To Degradation Of Glucocorticoid Receptor In Pituitary Adenomas

Cushing disease has a very high mortality rate and glucocorticoid resistance caused by GR down -regulation is one major reason of mortality. Although HIF1 alpha signaling and GR signaling are involved in the pathogenesis of pituitary adenomas, it's unclear whether and how these two essential pathways could cross-talk with each other. Here, we performed a comprehensive study to investigate the reciprocal effects of HIF1 alpha and GR on each other in AtT20 cell lines and explored the potential therapeutic effect of HIF1 alpha inhibitor in in-vivo mouse model. We find that hypoxia up-regulated the promoter activity, mRNA and protein levels of GR and the induced GR protein was localized in cytosol. On the other hand, GR activation by its agonist DEX increased HIF1 alpha protein through post-transcriptional mechanism. However, hypoxia and DEX show differential synergistic effects on HIF1 alpha and GR. In hypoxia-DEX condition, HIF1 alpha protein was further up-regulated but mainly localized in cytosol while GR was trapped and degraded in cytosol via UPS pathway. Further Co-IP experiments demonstrate that DNA binding domain of GR can interact with PASb domain of HIF1 alpha. In a in-vivo mouse model of Cushing's disease, HIF1 alpha inhibitor reduced HIF1 alpha and GR protein levels, reduced tumor size and lowered the plasma concentrations of ACTH and corticosterone. In summary, we find that a novel HIF1 alpha-GR crosstalk contributes to the pathogenesis of pituitary adenomas and HIF1 alpha inhibitor shows potential therapeutic effects for Cushing's disease.