title: Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas.
abstract: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M. To investigate the functional roles of H3K27M and PRC2 in DIPG pathogenesis, we profiled the epigenome of H3K27M-mutant DIPG cells and found that H3K27M associates with increased H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, the majority of the heterotypic H3K27M-K27ac nucleosomes colocalize with bromodomain proteins at the loci of actively transcribed genes, whereas PRC2 is excluded from these regions; this suggests that H3K27M does not sequester PRC2 on chromatin. Residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function. Finally, to examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, we performed treatments in vivo with BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Piunti
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Morgan
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Bartom
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Horbinski
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Marshall
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Rendleman
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Quanhong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Yoh-Hei
authors.initials: YH
authors.lastname: Takahashi
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Woodfin
authors.affiliation: Department of Medicine, Division of Pulmonology, and Department of Pediatrics, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Alexander V
authors.identifier: http://orcid.org/0000-0003-2879-3789
authors.initials: AV
authors.lastname: Misharin
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois, USA.
authors.forename: Nebiyu A
authors.initials: NA
authors.lastname: Abshiru
authors.affiliation: Department of Hematology, Oncology, Neuro-Oncology &Stem Cell Transplantation, Ann &Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Lulla
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Department of Surgery, Division of Pediatric Neurosurgery, Ann &Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.|Robert H. Lurie NCI Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Saratsis
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois, USA.
authors.forename: Neil L
authors.identifier: http://orcid.org/0000-0002-8815-3372
authors.initials: NL
authors.lastname: Kelleher
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie NCI Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie NCI Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D020295:Brain Stem Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism*; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D005910:Glioma / Q000235:genetics*; D042421:Histone Code / Q000187:drug effects / Q000235:genetics*; D006657:Histones / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008745:Methylation / Q000187:drug effects; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D016601:RNA-Binding Proteins; D014230:Triazoles; D063151:Polycomb Repressive Complex 2