MicroRNA-124 regulates glucocorticoid sensitivity by targeting phosphodiesterase 4B in diffuse large B cell lymphoma

Glucocorticoids (GCs) are chemotherapeutic drugs commonly used to treat hematological malignancies. However, a significant fraction of patients develop resistance to GCs during treatment. A better insight into how GC resistance develops is therefore needed. It was previously shown that cyclic AMP (cAMP) induces sensitivity to GCs by inhibiting the AKT/mTOR/MCL1 signaling, while high levels of phosphodiesterase 4B (PDE4B) reverse the effect of cAMP on GC responses in B-cell lymphoma. Here, we show that miR-124 influences GC-induced apoptosis by directly targeting PDE4B. Stable expression of miR-124 in diffuse large B cell lymphoma (DLBCL) cell lines diminished PDE4B expression. This was associated with increased cAMP levels, inhibition of the AKT/mTOR/MCL1 survival pathway, upregulation of GRα expression, and improved sensitivity to GCs in the presence of forskolin, an activator of adenylyl cyclase. Interestingly, miR-124 did not affect GC sensitivity in the absence of forskolin, indicating that the effect of this miRNA is accomplished via downregulation of PDE4B expression. Further, restoration of PDE4B expression in miR-124 cells rescued the phenotypic effect of this miRNA, demonstrating the critical role of PDE4B in miR-124-mediated regulation of the GC response. Our study supports the notion that miR-124 could be an attractive therapeutic target for overcoming GC resistance in DLBCL.