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.