The Regulatory Mechanism Invoived In Dexamethasone Induced FOXO1 Expression And PDX-1 Inhibition

Glucocorticoids are widely used in clinical therapy and steroiddiabetes is one of the side effects of glucocorticoid treatment.Dexamethasone has been proved to induce pancreaticβ-cells dysfunctionthrough FoxO1 expression and PDX-1 inhibition. However, themolecular mechanism involved in it is not fully understood. FoxA2, akey Forkhead family member which regulates gene expression inpancreatic islets, may take part in the regulation of FoxO1 and PDX-1gene expression. In this study, we used RINm5F cells to investigate thetranscription regulatory role of FoxA2 in dexamethasone induced FoxOlexpression and PDX-1 inhibition. Using promoter screening method, weselected several transcription factors in our study. Through gene overexpressionmethods and CHIP technique, we found that FoxA2 canpositively regulate FoxO1 expression by directly binding to FoxO1promoter (-1219/-1006bp) region. Moreover, dexamethasone alteredtranscription activity of FoxA2 from PDX-1 promoter to FoxO1 promoter, which led PDX-1 inhibition and FoxO1 accumulation. AndFoxO1 furtherlly suppressed PDX-1 by competing with FoxA2 forbinding to PDX-1 promoter. Besides, our research indicated thatdexamethasone didn't affect the expression and total transcriptionactivity of FoxA2 inβ-cells.In conclusion, our research suggests that FoxA2 mediatsdexamethasone induced FoxO1 expression and PDX-1 inhibition. Thisnovel viewpoint will replenish the molecular mechanism of steroiddiabetes andβ-cell dysfunction induced by dexamethasone.