Research ArticleCancer

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

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Science Signaling  22 Jan 2019:
Vol. 12, Issue 565, eaan8680
DOI: 10.1126/scisignal.aan8680

Targeting SHH-type medulloblastoma

Medulloblastoma is a brain tumor that occurs mostly in children and has few therapeutic options. Attempts to block the Sonic Hedgehog (SHH) pathway that drives various subtypes of the tumor have been unsuccessful clinically. Dobson et al. found a mechanism by which SHH signaling may be increased in some patients. In a new mouse model, the authors found that increased expression of the transcriptional repressor REST in cells that give rise to the disease supports a more aggressive disease course by promoting epigenetic repression of the genes that encode PTCH1 and PTEN, thereby enhancing proliferative and migratory signaling by SHH and the kinase AKT. These findings reveal potential therapeutic targets for patients with high-REST, SHH-type 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 (RESTTG) wherein conditional NeuroD2-controlled REST transgene expression in lineage-committed Ptch1+/− 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 Ptch1. Expression of Arrb1, which encodes β-arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed RESTTG cells compared with wild-type proliferating CGNPs. Lineage-committed RESTTG cells also had decreased GLI1 activity and increased histone H3K9 methylation at the Ptch1 locus, which correlated with premature silencing of Ptch1. These cells also had decreased expression of Pten, which encodes a negative regulator of the kinase AKT. Expression of PTCH1 and GLI1 were less, and ARRB1 was somewhat greater, in patient SHH-β than SHH-α MBs, whereas that of PTEN 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, PTCH1 silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.

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