CMKLR1/PKA signaling reinforces sonic hedgehog pathway to promote medulloblastoma pathogenesis

Aberrant Hedgehog signaling is a key driver of malignancies like medulloblastoma (MB), the most common pediatric brain tumor originating from cerebellar granule neuron progenitors with largely uncharacterized mechanisms. We found here that the G protein-coupled receptor, chemokine-like receptor 1 (CMKLR1), is upregulated and correlates with the development of Sonic Hedgehog (SHH)-subtype MB. SHH and the downstream transcription factor Gli2 license the expression of CMKLR1, which promotes the growth and migration of cells by activating Gα(i)βγ and subsequently the PI3K/Akt signal pathway. SHH/Gli also transcriptionally represses Regulator of G Protein Signaling 16 (RGS16), a known suppressor of Gα(i). Meanwhile, CMKLR1/Gα(i) signaling inactivates protein kinase A (PKA), reduces PKA-catalyzed phosphorylation of Gli2, and circumvents its proteasomal degradation, thus forming a feedback circuit in medulloblastoma cells. Consistently, CMKLR1 ablation suppresses the in vivo development of SHH subtype MB, which is counteracted by further silencing of the PKA catalytic subunit. These findings provide novel insights into the oncogenic network of Hedgehog pathway-driven cancer.