Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG.

Acetylation Animals Antineoplastic Agents / pharmacology Brain Stem Neoplasms / drug therapy Carbazoles / pharmacology Cell Cycle Proteins / genetics Cell Line, Tumor Child Chromatin / chemistry DNA-Binding Proteins / genetics Diffuse Intrinsic Pontine Glioma / drug therapy Drug Synergism E2F1 Transcription Factor / genetics Epigenesis, Genetic Epigenome High Mobility Group Proteins / genetics Histones / antagonists & inhibitors Humans Methylation Mice Neuroglia / drug effects Panobinostat / pharmacology Primary Cell Culture Retinoblastoma Protein / genetics Signal Transduction Survival Analysis Transcription Factors / genetics Transcriptional Elongation Factors / genetics Tumor Suppressor Protein p53 / genetics Xenograft Model Antitumor Assays
DIPG E2F1 EZH2 H3K27M HDAC anticancer therapy brainstem glioma facilitates chromatin transcription complex pediatric cancer xenograft model

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
13 04 2021
Historique:
received: 23 07 2020
revised: 24 12 2020
accepted: 24 03 2021
entrez: 14 4 2021
pubmed: 15 4 2021
medline: 15 2 2022
Statut: ppublish

Résumé

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.

Identifiants

DOI: 10.1016/j.celrep.2021.108994 PMID: 33852836
pubmed: 33852836
pii: S2211-1247(21)00308-9
doi: 10.1016/j.celrep.2021.108994
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
CBLC137 0
Carbazoles 0
Cell Cycle Proteins 0
Chromatin 0
DNA-Binding Proteins 0
E2F1 Transcription Factor 0
E2F1 protein, human 0
High Mobility Group Proteins 0
Histones 0
Retinoblastoma Protein 0
SSRP1 protein, human 0
SUPT16H protein, human 0
TP53 protein, human 0
Transcription Factors 0
Transcriptional Elongation Factors 0
Tumor Suppressor Protein p53 0
Panobinostat 9647FM7Y3Z

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

108994

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests K.G. and A.V.G. are co-inventors on patents describing CBL0137. The remaining authors declare no competing interests.

Auteurs

Anahid Ehteda (A)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Sandy Simon (S)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Laura Franshaw (L)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Federico M Giorgi (FM)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Jie Liu (J)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Swapna Joshi (S)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Jourdin R C Rouaen (JRC)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Chi Nam Ignatius Pang (CNI)

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.

Ruby Pandher (R)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Chelsea Mayoh (C)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.

Yujie Tang (Y)

State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Aaminah Khan (A)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Caitlin Ung (C)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Ornella Tolhurst (O)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Anne Kankean (A)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Elisha Hayden (E)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Rebecca Lehmann (R)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Sylvie Shen (S)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Anjana Gopalakrishnan (A)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Peter Trebilcock (P)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Katerina Gurova (K)

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Andrei V Gudkov (AV)

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Murray D Norris (MD)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; Centre for Childhood Cancer Research, University of New South Wales, Sydney, NSW, Australia.

Michelle Haber (M)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.

Orazio Vittorio (O)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.

Maria Tsoli (M)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia. Electronic address: mtsoli@ccia.org.au.

David S Ziegler (DS)

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia; Kid's Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia. Electronic address: d.ziegler@unsw.edu.au.

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Classifications MeSH

questionsmedicales.fr › Métabolisme › Acylation › Acétylation › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Eucaryotes › Animaux › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Tumeurs sous-tentorielles › Tumeurs du tronc cérébral › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérocycliques 3 noyaux › Carbazoles › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Tumeurs sous-tentorielles › Tumeurs du tronc cérébral › Gliome infiltrant du tronc cérébral › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Interactions médicamenteuses › Synergie des médicaments › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription E2F › Facteur de transcription E2F1 › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Épigénome › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › Protéines HMG › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Métabolisme › Alkylation › Méthylation › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Cellules › Névroglie › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indoles › Panobinostat › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Techniques de culture › Techniques de culture cellulaire › Culture de cellules primaires › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine du rétinoblastome › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs d'élongation transcriptionnelle › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › Dual targeting of the epigenome via FACT...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Dual targeting of the epigenome via FACT...