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Cell Rep. 2019 Feb 26;26(9):2274-2281.e5. doi: 10.1016/j.celrep.2019.01.109.

Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma.

Author information

1
Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
2
Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
3
Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan; Department of Epidemiology, Nagoya University School of Medicine, Nagoya, Japan.
4
Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan.
5
Division of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
6
Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan. Electronic address: katot@med.kitasato-u.ac.jp.
7
Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. Electronic address: anatsume@med.nagoya-u.ac.jp.

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.

KEYWORDS:

RET finger protein; chemoresistance; cis-regulatory elements; glioma; histone H3K27

PMID:
30811978
DOI:
10.1016/j.celrep.2019.01.109
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