Targeting novel bromodomain protein in colorectal cancer

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07214
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: The University of Tokyo
• Principal Investigator: Yamaguchi Kiyoshi 東京大学, 医科学研究所, 特任講師 (50466843)
• Co-Investigator(Kenkyū-buntansha): 古川 洋一 東京大学, 医科学研究所, 教授 (20272560)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 大腸がん / 分子標的治療 / エピジェネティクス / ブロモドメイン / 遺伝子発現

Outline of Final Research Achievements

Our recent studies have disclosed that BRD8, a member of bromodomain family proteins, is accumulated in cancer cells, and that BRD8 plays a role in transcriptional events. However, the fundamental function of its bromodomain is largely unknown. In this study, we found that BRD8 interacts with histone protein(s) in cells, and their interactions are insensitive to the BET (bromodomains and extra-terminal domain) inhibitor which targets a bromodomain in BRD4. In addition, we generated BRD8-knockout colorectal cancer cells using CRISPR-Cas9 system, and examined in vitro spheroid formation of the cells. The spheroid formation was significantly suppressed by the knockout of BRD8. Our data suggest that BRD8 might be a novel therapeutic target for colorectal cancer.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

アセチル化修飾を受けたタンパク質を認識するブロモドメインは、有望な創薬（druggable）ターゲットである。BRD8はアミノ酸配列の違いから、創薬開発が進んでいるBETファミリー(BRD2、BRD3、BRD4およびBRDT)のブロモドメインとは区別され、その生物学的な役割は不明な点が多かった。これまでの我々の研究成果は、がんの発生や進展におけるBRD8の関与を裏付けるものであり、今後、BRD8のエピジェネティック情報認識機能や転写調節機能を標的（阻害）とする新しい抗がん剤開発への展開が期待される。