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Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG
- Source :
- Cell Reports, Vol 35, Iss 2, Pp 108994-(2021)
- Publication Year :
- 2021
-
Abstract
- Summary: 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.
- Subjects :
- 0301 basic medicine
xenograft model
Cell Cycle Proteins
Retinoblastoma Protein
Epigenesis, Genetic
Histones
Epigenome
Mice
chemistry.chemical_compound
0302 clinical medicine
facilitates chromatin transcription complex
HDAC
Panobinostat
Brain Stem Neoplasms
Biology (General)
Child
EZH2
Histone deacetylase inhibitor
High Mobility Group Proteins
Acetylation
Drug Synergism
Chromatin
pediatric cancer
DNA-Binding Proteins
DIPG
Transcriptional Elongation Factors
Neuroglia
Signal Transduction
medicine.drug_class
QH301-705.5
Primary Cell Culture
Carbazoles
Antineoplastic Agents
Methylation
General Biochemistry, Genetics and Molecular Biology
Chromatin remodeling
03 medical and health sciences
H3K27M
Cell Line, Tumor
medicine
Animals
Humans
anticancer therapy
Histone H3 acetylation
Diffuse Intrinsic Pontine Glioma
brainstem glioma
Survival Analysis
Xenograft Model Antitumor Assays
Pediatric cancer
030104 developmental biology
chemistry
E2F1
Cancer research
Histone deacetylase
Tumor Suppressor Protein p53
E2F1 Transcription Factor
030217 neurology & neurosurgery
Transcription Factors
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell Reports, Vol 35, Iss 2, Pp 108994-(2021)
- Accession number :
- edsair.doi.dedup.....ccbee79680e90f0fba780fc68415fa1d