Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma.
Animals
Antineoplastic Agents, Alkylating
/ therapeutic use
Apoptosis
/ genetics
Cell Division
/ genetics
Cell Line, Tumor
DNA-Binding Proteins
/ genetics
Down-Regulation
Drug Resistance, Neoplasm
/ genetics
Female
Gene Knockdown Techniques
Glioblastoma
/ drug therapy
Histones
/ metabolism
Humans
Male
Mice, Inbred BALB C
Nuclear Proteins
/ genetics
Oxidative Stress
Prognosis
RNA, Small Interfering
Regulatory Sequences, Nucleic Acid
Temozolomide
/ therapeutic use
RET finger protein
chemoresistance
cis-regulatory elements
glioma
histone H3K27
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 02 2019
26 02 2019
Historique:
received:
12
07
2018
revised:
06
01
2019
accepted:
29
01
2019
entrez:
28
2
2019
pubmed:
28
2
2019
medline:
17
4
2020
Statut:
ppublish
Résumé
RET finger protein (RFP) forms a complex with histone deacetylase 1, resulting in aberrant deacetylation of H3K27ac and dysregulation of cis-regulatory elements. We evaluated the modulatory effects of RFP knockdown on cis-regulatory elements, gene expression, and chemosensitivity to temozolomide both in glioblastoma cells and in an intracranial glioblastoma model. The combination of RFP knockdown and temozolomide treatment markedly suppressed the glioblastoma cell growth due to oxidative stress and aberrant cell cycle and increased survival time in mice with glioblastoma. ChIP-seq and RNA-seq revealed that RFP knockdown increased or decreased activity of numerous cis-regulatory elements that lie adjacent to genes that control functions such as apoptosis, mitosis, DNA replication, and cell cycle: FOXO1, TBP2, and PARPBP. This study suggests that RFP contributes to chemoresistance via aberrant deacetylation of histone H3 at K27, whereas dysregulation of RFP-associated cis-regulatory elements in glioma and RFP knockdown combined with temozolomide is an effective treatment strategy for lethal glioma.
Identifiants
pubmed: 30811978
pii: S2211-1247(19)30146-9
doi: 10.1016/j.celrep.2019.01.109
pii:
doi:
Substances chimiques
Antineoplastic Agents, Alkylating
0
DNA-Binding Proteins
0
Histones
0
Nuclear Proteins
0
PARPBP protein, human
0
RNA, Small Interfering
0
TRIM27 protein, human
0
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2274-2281.e5Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.