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
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.
