Elucidating anti-tumor effect of Bromodomain protein in refractory renal cell carcinoma

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18587
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Kagoshima University
• Principal Investigator: SAKAGUCHI Takashi 鹿児島大学, 鹿児島大学病院, 医員 (70779008)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 腎細胞癌 / スニチニブ耐性 / ブロモドメイン蛋白 / BRD4

Outline of Final Research Achievements

Based on the gene expression analyses of sunitinib-resistant ccRCC cells, bromodomain containing 4 (BRD4), a member of the bromodomain family proteins, was identified as a promising therapeutic target. Analysis of The Cancer Genome Atlas (TCGA) ccRCC cohort showed that patients with high BRD4 expression had shorter overall survival than those with low expression. JQ1 treatment significantly inhibited tumor growth of sunitinib-sensitive and -resistant ccRCC cells in part through MYC regulation. Chromatin immunoprecipitation assays revealed that SCG5, SPOCD1, RGS19, and ARHGAP22 may be promising BRD4 targets, particularly in sunitinib-resistant ccRCC cells. These results identified these oncogenes as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.

Free Research Field

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Academic Significance and Societal Importance of the Research Achievements

本研究によりスニチニブ抵抗性腎癌細胞においてBRD4阻害により遮断される分子経路の解明は、JQ1抵抗性メカニズムの理解を深めることに繋がった。またJQ1投与により特にスニチニブ抵抗性腎癌細胞において発現が抑制されている遺伝子群や分子経路を探索・解明できた。今後のスニチニブ抵抗性腎癌における新たな治療戦略の提案を行うことが出来たため、社会的な意義は大きい。