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2. ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells.

Author

Park NI, Guilhamon P, Desai K, McAdam RF, Langille E, O'Connor M, Lan X, Whetstone H, Coutinho FJ, Vanner RJ, Ling E, Prinos P, Lee L, Selvadurai H, Atwal G, Kushida M, Clarke ID, Voisin V, Cusimano MD, Bernstein M, Das S, Bader G, Arrowsmith CH, Angers S, Huang X, Lupien M, and Dirks PB

Subjects
Base Sequence, Basic Helix-Loop-Helix Transcription Factors genetics, Brain Neoplasms genetics, Carcinogenesis genetics, Cell Differentiation genetics, Disease Progression, Enhancer Elements, Genetic genetics, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Humans, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Neurons metabolism, Promoter Regions, Genetic genetics, Protein Binding, Sequence Analysis, RNA, Up-Regulation genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Brain Neoplasms pathology, Carcinogenesis pathology, Cell Lineage, Chromatin metabolism, Glioblastoma pathology, Neurons pathology
Abstract

Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1 hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1 lo GSCs do not. Increasing ASCL1 levels in ASCL1 lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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3. Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells.

Author

Dolma S, Selvadurai HJ, Lan X, Lee L, Kushida M, Voisin V, Whetstone H, So M, Aviv T, Park N, Zhu X, Xu C, Head R, Rowland KJ, Bernstein M, Clarke ID, Bader G, Harrington L, Brumell JH, Tyers M, and Dirks PB

Subjects
Animals, Autophagy, Brain Neoplasms metabolism, Cell Differentiation drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Gene Expression Regulation, Neoplastic drug effects, Glioblastoma metabolism, Humans, Mice, Neoplastic Stem Cells cytology, Neoplastic Stem Cells drug effects, Neural Stem Cells cytology, Neural Stem Cells pathology, Receptors, Dopamine D4 antagonists & inhibitors, Signal Transduction drug effects, Small Molecule Libraries pharmacology, Survival Analysis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Neural Stem Cells drug effects, Receptors, Dopamine D4 metabolism, Small Molecule Libraries administration & dosage
Abstract

Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G0/G1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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4. MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.

Author

Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, Remke M, Li R, Takayama N, Desai K, Lee L, Lan X, Park NI, Barsyte-Lovejoy D, Smil D, Sturm D, Kushida MM, Head R, Cusimano MD, Bernstein M, Clarke ID, Dick JE, Pfister SM, Rich JN, Arrowsmith CH, Taylor MD, Jabado N, Bazett-Jones DP, Lupien M, and Dirks PB

Subjects
Adolescent, Adult, Animals, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms mortality, Brain Neoplasms pathology, Cell Differentiation, Cell Proliferation, Child, Child, Preschool, DNA Methylation, DNA-Binding Proteins genetics, Drug Design, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma mortality, Glioblastoma pathology, Histones genetics, Humans, Kaplan-Meier Estimate, Mice, Inbred NOD, Mice, SCID, Molecular Targeted Therapy, Mutation, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Prognosis, RNA Interference, Signal Transduction, Time Factors, Transfection, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Young Adult, Brain Neoplasms metabolism, Cell Self Renewal drug effects, Chromatin Assembly and Disassembly drug effects, DNA-Binding Proteins metabolism, Glioblastoma metabolism, Histones metabolism, Neoplastic Stem Cells metabolism
Abstract

Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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