Bromodomain protein BRD8 regulates cell cycle progression in colorectal cancer cells through a TIP60-independent regulation of the pre-RC complex

Kiyoshi Yamaguchi; Saya Nakagawa; Akari Saku; Yumiko Isobe; Rui Yamaguchi; Paul Sheridan; Kiyoko Takane; Tsuneo Ikenoue; Chi Zhu; Masashi Miura; Yuya Okawara; Satoru Nagatoishi; Hiroko Kozuka-Hata; Masaaki Oyama; Susumu Aikou; Yuka Ahiko; Dai Shida; Kouhei Tsumoto; Satoru Miyano; Seiya Imoto; Yoichi Furukawa

iScience (Apr 2023)

Bromodomain protein BRD8 regulates cell cycle progression in colorectal cancer cells through a TIP60-independent regulation of the pre-RC complex

Kiyoshi Yamaguchi,
Saya Nakagawa,
Akari Saku,
Yumiko Isobe,
Rui Yamaguchi,
Paul Sheridan,
Kiyoko Takane,
Tsuneo Ikenoue,
Chi Zhu,
Masashi Miura,
Yuya Okawara,
Satoru Nagatoishi,
Hiroko Kozuka-Hata,
Masaaki Oyama,
Susumu Aikou,
Yuka Ahiko,
Dai Shida,
Kouhei Tsumoto,
Satoru Miyano,
Seiya Imoto,
Yoichi Furukawa

Affiliations

Kiyoshi Yamaguchi: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Corresponding author
Saya Nakagawa: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Akari Saku: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Yumiko Isobe: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Rui Yamaguchi: Division of Cancer Systems Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan; Division of Cancer Informatics, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
Paul Sheridan: Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Kiyoko Takane: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Tsuneo Ikenoue: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Chi Zhu: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Masashi Miura: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Yuya Okawara: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Satoru Nagatoishi: Project Division of Advanced Biopharmaceutical Science, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Hiroko Kozuka-Hata: Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Masaaki Oyama: Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Susumu Aikou: Division of Frontier Surgery, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Yuka Ahiko: Division of Frontier Surgery, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Dai Shida: Division of Frontier Surgery, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Kouhei Tsumoto: Project Division of Advanced Biopharmaceutical Science, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
Satoru Miyano: Department of Integrated Analytics, M&D Data Science Center, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Seiya Imoto: Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Yoichi Furukawa: Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Corresponding author

Journal volume & issue: Vol. 26, no. 4
p. 106563

Abstract

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Summary: Bromodomain-containing protein 8 (BRD8) is a subunit of the NuA4/TIP60-histone acetyltransferase complex. Although BRD8 has been considered to act as a co-activator of the complex, its biological role remains to be elucidated. Here, we uncovered that BRD8 accumulates in colorectal cancer cells through the inhibition of ubiquitin-dependent protein degradation by the interaction with MRG domain binding protein. Transcriptome analysis coupled with genome-wide mapping of BRD8-binding sites disclosed that BRD8 transactivates a set of genes independently of TIP60, and that BRD8 regulates the expression of multiple subunits of the pre-replicative complex in concert with the activator protein-1. Depletion of BRD8 induced cell-cycle arrest at the G1 phase and suppressed cell proliferation. We have also shown that the bromodomain of BRD8 is indispensable for not only the interaction with histone H4 or transcriptional regulation but also its own protein stability. These findings highlight the importance of bromodomain as a therapeutic target.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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