miR‐221/222 suppression induced by activation of the cAMP/PKA/CREB1 pathway is required for cAMP‐induced bidirectional differentiation of glioma cells

Factors that increase cAMP levels can induce lineage‐specific differentiation of glioma cells into astrocyte‐like cells. However, the differentiation pattern and underlying mechanisms remain unclear. Here, we find that cAMP/protein kinase A (PKA)/cAMP responsive element binding protein 1 (CREB1)‐induced miR‐221/222 suppression contributes to the neuron‐like differentiation of gliomas. cAMP agonists selectively induced neuron‐ and astrocyte‐like but not oligodendrocyte‐like differentiation of C6 glioma cells. PKA inhibitors and CREB1 knockout blocked neuron‐like differentiation of glioma cells. cAMP inhibited miR‐221/222 in a PKA/CREB1‐dependent manner. Importantly, both in vitro and in vivo assays demonstrated that transcriptional suppression of miR‐221/222 is required for neuronal differentiation of glioma cells. Our findings suggest that increasing cAMP levels can induce bidirectional differentiation of glioma cells. Furthermore, the miR‐221/222 cluster acts as an epigenetic brake during glioma differentiation. cAMP selectively induces astrocyte‐ and neuron‐like differentiation of glioma cells. cAMP stimulators suppress miR‐221/222 in a cAMP/PKA/CREB1‐dependent manner. MiR‐221/222 cluster suppression results in P27 upregulation which contributes to the cAMP‐induced bidirectional differentiation of glioma cells.