Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma

In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-β (infants) subgroups. Neuronal maturation is greater in SHH-β than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model ( ) wherein conditional -controlled transgene expression in lineage-committed cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context-specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at Expression of , which encodes β-arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed cells compared with wild-type proliferating CGNPs. Lineage-committed cells also had decreased GLI1 activity and increased histone H3K9 methylation at the locus, which correlated with premature silencing of These cells also had decreased expression of , which encodes a negative regulator of the kinase AKT. Expression of and were less, and was somewhat greater, in patient SHH-β than SHH-α MBs, whereas that of was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.