期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：34
DOI：10.1073/pnas.2202821119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Cerebellar development relies on a precise coordination of metabolic signaling, epigenetic signaling, and transcriptional regulation. Here, we reveal that O-GlcNAc transferase (OGT) regulates cerebellar neurogenesis and medulloblastoma growth via a Sonic hedgehog (Shh)-Smo-Gli2 pathway. We identified Gli2 as a substrate of OGT, and unveiled cross-talk between O-GlcNAc and epigenetic signaling as a means to regulate Gli2 transcriptional activity. Moreover, genetic ablation or chemical inhibition of OGT significantly suppresses tumor progression and increases survival in a mouse model of Shh subgroup medulloblastoma. Taken together, the data in our study provide a line of inquiry to decipher the signaling mechanisms underlying cerebellar development, and highlights a potential target to investigate related pathologies, such as medulloblastoma.
Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh subgroup of medulloblastoma. Specifically, OGT regulates the neurogenesis of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases. Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.
