RNF138 polyubiquitinates glioma-associated oncogene 1 on K815/K942 to suppress Sonic Hedgehog signaling in medulloblastoma.

Sonic hedgehog (SHH) signaling pathway serves as a critical regulator for embryonic development and tumorigenesis. Medulloblastoma (MB) is one of the most common malignancy in cerebella of pediatric populations, and mutation and aberrant activation of key components in SHH signaling pathway drive the oncogenesis of MBSHH, accompanied by activation of the effector transcription factor GLI1. We have previously uncovered that phosphorylation of human GLI1 on Ser937 controls the oncogenesis of MBSHH. To explore further the post-translational modifications in GLI1, we performed proteomics analysis and found that GLI1 interacted with RING family ubiquitin E3 ligase RNF138. RNF138 directly polyubiquitinated GLI1 on lysine residues K815 and K942 and in turn destabilized GLI1 to inactivate SHH signaling. As a result, low expression of RNF138 in human MBSHH correlated with high GLI1 protein level, whereas overexpression of RNF138 downregulated GLI1 to suppress the growth of human MBSHH Daoy cells xenografts. Taken together, these results uncover GLI1 polyubiquitination by RNF138 as a hitherto uncharacterized mechanism governing SHH signaling and may serve as an additional therapeutic target in SHH-driven malignancies.