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

• Type of Material: Article
• Authors: Tara HW Dobson, University of Texas, M.D. Anderson Cancer Center; Rong-Hua Tao, University of Texas, M.D. Anderson Cancer Center; Jyothishmathi Swaminathan, University of Texas, M.D. Anderson Cancer Center; Shinji Maegawa, University of Texas, M.D. Anderson Cancer Center; Shavali Shaik, University of Texas, M.D. Anderson Cancer Center; Javiera Bravo-Alegria, University of Texas, M.D. Anderson Cancer Center; Ajay Sharma, University of Texas, M.D. Anderson Cancer Center; Bridget Kennis, University of Texas, M.D. Anderson Cancer Center; Yanwen Yang, University of Texas, M.D. Anderson Cancer Center; Keri Callegari, University of Texas, M.D. Anderson Cancer Center; Amanda R Haltom, University of Texas, M.D. Anderson Cancer Center; Pete Taylor, University of Texas, M.D. Anderson Cancer Center; Mari Kogiso, Baylor College of Medicine; Lin Qi, Baylor College of Medicine; Soumen Khatua, University of Texas, M.D. Anderson Cancer Center; Stewart Goldman, Northwestern University; Rishi R Lulla, Northwestern University; Jason Fangusaro, Emory University; Tobey J MacDonald, Emory University; Xiao-Nan Li, Northwestern University; Cynthia Hawkins, Hospital for Sick Children, Toronto; Veena Rajaram, UT Southwestern Medical Center; Vidya Gopalakrishnan, University of Texas, M.D. Anderson Cancer Center
• Language: English
• Date: 2019-01-22
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• Final Published Version (URL): http://dx.doi.org/10.1126/scisignal.aan8680
• Title of Journal or Parent Work: SCIENCE SIGNALING
• Volume: 12
• Issue: 565
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (NIH, 5R01-NS-079715-01 and 5R03NS077021-01 to V.G., and R01 CA185402 to X.-N.L.), American Cancer Society (RSG-09-273-01-DDC to V.G.), Cancer Prevention Research Institute of Texas (CPRIT-RP150301 to V.G.), Addis Faith Foundation and Rally Foundation for Childhood Cancers (to VG.), and The University of Texas MD Anderson Cancer Center-CCE Scholar Program (to T.D.).
• Keywords: REGULATOR; Life Sciences & Biomedicine; REST/NRSF; G9A; EXPRESSION; TARGET; Cell Biology; Biochemistry & Molecular Biology; SIGNALING PATHWAY; PROLIFERATION; Science & Technology; PROTEIN; SONIC-HEDGEHOG; MOLECULAR SUBGROUPS

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- (children 3 to 16 years) and SHH- (infants) subgroups. Neuronal maturation is greater in SHH- than SHH- tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (REST TG ) 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 -arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed REST TG cells compared with wild-type proliferating CGNPs. Lineage-committed REST TG 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- than SHH- 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.