TOP2B Enzymatic Activity on Promoters and Introns Modulates Multiple Oncogenes in Human Gliomas.
Animals
Brain Neoplasms
/ enzymology
DNA Topoisomerases, Type II
/ physiology
Epigenesis, Genetic
/ physiology
Gene Expression Regulation, Neoplastic
Glioma
/ enzymology
Humans
Introns
/ physiology
Mice
Oncogenes
/ physiology
Poly-ADP-Ribose Binding Proteins
/ physiology
Promoter Regions, Genetic
/ physiology
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 10 2021
15 10 2021
Historique:
received:
25
01
2021
revised:
07
05
2021
accepted:
28
07
2021
pubmed:
27
8
2021
medline:
2
4
2022
entrez:
26
8
2021
Statut:
ppublish
Résumé
The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors. To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes. We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.
Identifiants
pubmed: 34433651
pii: 1078-0432.CCR-21-0312
doi: 10.1158/1078-0432.CCR-21-0312
pmc: PMC8818263
mid: NIHMS1768468
doi:
Substances chimiques
Poly-ADP-Ribose Binding Proteins
0
DNA Topoisomerases, Type II
EC 5.99.1.3
TOP2B protein, human
EC 5.99.1.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5669-5680Subventions
Organisme : NIH HHS
ID : DP5 OD021356
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221747
Pays : United States
Informations de copyright
©2021 The Authors; Published by the American Association for Cancer Research.
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