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

Melissa Ranjit, Masaki Hirano, Kosuke Aoki, Yusuke Okuno, Fumiharu Ohka, Akane Yamamichi, Akira Kato, Sachi Maeda, Kazuya Motomura, Keitaro Matsuo, Atsushi Enomoto, Yasushi Ino, Tomoki Todo, Masahide Takahashi, Toshihiko Wakabayashi, Takuya Kato, Atsushi Natsume

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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.

Original languageEnglish
Pages (from-to)2274-2281.e5
JournalCell Reports
Volume26
Issue number9
DOIs
Publication statusPublished - 26-02-2019

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    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. (2019). Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma. Cell Reports, 26(9), 2274-2281.e5. https://doi.org/10.1016/j.celrep.2019.01.109