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

Abstract

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 showthatmiR-124 influences GC-induced apoptosis by directly targeting PDE4B. Stable expression ofmiR-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 thismiRNA is accomplished via downregulation of PDE4B expression. Further, restoration of PDE4B expression inmiR-124 cells rescued the phenotypic effect of thismiRNA, 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.