Hypoxia- and dexamethasone-dependent HIF1α-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 HIF1α 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 HIF1α and GR on each other in AtT20 cell lines and explored the potential therapeutic effect of HIF1α 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 HIF1α protein through post-transcriptional mechanism. However, hypoxia and DEX show differential synergistic effects on HIF1α and GR. In hypoxia-DEX condition, HIF1α 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 HIF1α. In a in-vivo mouse model of Cushing's disease, HIF1α inhibitor reduced HIF1α and GR protein levels, reduced tumor size and lowered the plasma concentrations of ACTH and corticosterone. In summary, we find that a novel HIF1α-GR crosstalk contributes to the pathogenesis of pituitary adenomas and HIF1α inhibitor shows potential therapeutic effects for Cushing's disease.