Investigate the Role of O-GlcNAcylation in Hedgehog Pathway and Medulloblastoma
Open AccessThe Hedgehog (HH) pathway plays a pivotal role in brain development. Perturbation of the HH pathway and activation of glioma-associated oncogene (GLI), a dedicated transcription factor in the HH pathway, is responsible for approximately 30% of medulloblastoma (MB), a common type of pediatric brain tumor. However, the underlying mechanism of abnormal activation of HH pathway in MB is still not fully understood. Here, we identified a previously unknown mechanism by which the HBP pathway is regulated by glucose-sensing O-GlcNAcylation. O-GlcNAcylation corresponds to the attachment of UDP-GlcNAc to specific Ser/Thr residues of target proteins. The increased total O-GlcNAcylation is a general characteristic of cancers, and O-GlcNAcylation is a central communicator of nutritional status to control key signaling and metabolic pathways that regulate multiple cancer cell phenotypes. But whether O-GICNAC signaling regulates the HH pathway and medulloblastoma is still unknown. We found that the HH pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of HH pathway (GLI1) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at 4 serine residues (S97, S543, S545 and S963). GLI1 O-GlcNAcylation blocks its interaction with SUFU, promoting its nuclear localization and target gene transcription. Finally, we confirmed that glucose-induced GLI1 O-GlcNAcylation and activation promoted medulloblastoma cancer cell growth. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the HH pathway and MB development. Additionally, we will use patient-derived xenograft models to examine the effects of O-GlcNAcylation-targeted inhibition in medulloblastoma treatments. This project will provide new clues for the regulation of HH pathway and provide new theoretical basses for the diagnosis and treatment of SHH subtype medulloblastoma.
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Alhumaidi_gwu_0075M_15207.pdf | 2021-01-10 | Open Access |
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