RRC ID 60133
Author Ranjit M, Hirano M, Aoki K, Okuno Y, Ohka F, Yamamichi A, Kato A, Maeda S, Motomura K, Matsuo K, Enomoto A, Ino Y, Todo T, Takahashi M, Wakabayashi T, Kato T, Natsume A.
Title Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma.
Journal Cell Rep
Abstract 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.
Volume 26(9)
Pages 2274-2281.e5
Published 2019-2-26
DOI 10.1016/j.celrep.2019.01.109
PII S2211-1247(19)30146-9
PMID 30811978
MeSH Animals Antineoplastic Agents, Alkylating / therapeutic use Apoptosis / genetics Cell Division / genetics Cell Line, Tumor DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Down-Regulation Drug Resistance, Neoplasm / genetics* Female Gene Knockdown Techniques Glioblastoma / drug therapy Glioblastoma / genetics* Glioblastoma / metabolism Glioblastoma / mortality Histones / metabolism Humans Male Mice, Inbred BALB C Nuclear Proteins / genetics Nuclear Proteins / metabolism* Oxidative Stress Prognosis RNA, Small Interfering Regulatory Sequences, Nucleic Acid Temozolomide / therapeutic use
IF 7.815
Times Cited 2
Human and Animal Cells T98G(RCB1954)