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

Abstract

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 conditionalNeuroD2-controlledRESTtransgene expression in lineage-committedPtch1+/−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 atPtch1. Expression ofArrb1, which encodes β-arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committedRESTTGcells compared with wild-type proliferating CGNPs. Lineage-committedRESTTGcells also had decreased GLI1 activity and increased histone H3K9 methylation at thePtch1locus, which correlated with premature silencing ofPtch1. These cells also had decreased expression ofPten, which encodes a negative regulator of the kinase AKT. Expression ofPTCH1andGLI1were less, andARRB1was somewhat greater, in patient SHH-β than SHH-α MBs, whereas that ofPTENwas 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,PTCH1silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.

ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures

“…In addition to NB, high expression levels of REST have been detected in other cancers including glioma and medulloblastoma (Dobson et al, 2019;Taylor et al, 2012;Zhang et al, 2016). This implicates REST as a key transcription factor important in normal neurogenesis that is hijacked by cancer cells to promote proliferation/survival.…”

“…Genome mapping of REST suggests that its intricate function in regulating gene expression depends on co-factors including SIN3A, the CoREST complex, Polycomb Repressive Complex 1 (PRC1), and PRC2 (Dietrich et al, 2012;McGann et al, 2014;Rockowitz et al, 2014). REST is overexpressed in several aggressive tumors of the nervous system, including neuroblastoma (stage 4 MYCN non-amplified) (Liang et al, 2014), medulloblastoma, and glioblastoma (Dobson et al, 2019;Taylor et al, 2012;Zhang et al, 2016).…”

News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

“…Inhibition of either REST or the enzyme decreased cancer aggressiveness [48]. An additional study of medulloblastoma revealing the chromatin compaction induced by REST via Akt activation identified a new potential subgroup of specific therapeutic targets [49].…”

Downregulation of miR‐326 and its host gene β‐arrestin1 induces pro‐survival activity of E2F1 and promotes medulloblastoma growth

“…Moreover, ARRB1 expression inversely correlates with proliferation of GCPs derived from a transgenic mouse model involving RE1-silencing transcription factor (REST), a transcriptional repressor of neuronal differentiation [32]. For this reason, the fact that miR-326 and ARRB1 appear to exert convergent tumor-suppressive effects in human MBs is by no means incompatible with its demonstrated oncogenic effects in other cancer cells [73][74][75][76]71].…”

“…ARRB1, as miR-326, is involved in neuronal differentiation, where its up-regulated expression in cerebellar GCPs and in neural stem cells halts proliferation and induces growth arrest [25,26]. Notably, under-expression of ARRB1 has been documented in brain tumors [23,[27][28][29][30][31][32].…”