TY - JOUR
T1 - Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma
AU - Ranjit, Melissa
AU - Hirano, Masaki
AU - Aoki, Kosuke
AU - Okuno, Yusuke
AU - Ohka, Fumiharu
AU - Yamamichi, Akane
AU - Kato, Akira
AU - Maeda, Sachi
AU - Motomura, Kazuya
AU - Matsuo, Keitaro
AU - Enomoto, Atsushi
AU - Ino, Yasushi
AU - Todo, Tomoki
AU - Takahashi, Masahide
AU - Wakabayashi, Toshihiko
AU - Kato, Takuya
AU - Natsume, Atsushi
N1 - Funding Information:
Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Chemistry for Multimolecular Crowding Biosystems” ( JSPS KAKENHI Grant 17928985 ).
Publisher Copyright:
© 2019 The Authors
PY - 2019/2/26
Y1 - 2019/2/26
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2019.01.109
DO - 10.1016/j.celrep.2019.01.109
M3 - Article
C2 - 30811978
AN - SCOPUS:85061437027
SN - 2211-1247
VL - 26
SP - 2274-2281.e5
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -