進行腎細胞癌においてブロモドメイン蛋白BRD4阻害剤JQ1は複数の有望な予後予測因子を制御する

• Material Type: 博士論文
• Title: 進行腎細胞癌においてブロモドメイン蛋白BRD4阻害剤JQ1は複数の有望な予後予測因子を制御する
• Author/Editor: 坂口, 大
• Author Heading: 坂口, 大 サカグチ, タカシ
• Publication, Distribution, etc.: 鹿児島大学
• Publication Date: 2018-05-01
• Publication Date (W3CDTF): 2018-05-01
• Alternative Title: Bromodomain protein BRD4 inhibitor JQ1 regulates potential prognostic molecules in advanced renal cell carcinoma
• Periodical title: Oncotarget
• No. or year of volume/issue: 9 33
• Volume: 9
• Issue: 33
• Pages: 23003-23017
• Degree grantor/type: 鹿児島大学
• Date Granted: 2018-11-20
• Dissertation Number: 甲総研第486号
• Degree Type: 博士(医学); Doctor of Philosophy in Medical Science
• Text Language Code: eng
• Subject Heading: bromodomain; BRD4; JQ1; sunitinib resistance; renal cell carcinoma
• Target Audience: 一般
• Note (General): 博士論文全文, 博士論文要旨, 最終試験結果の要旨, 論文審査の要旨; Sunitinib is a standard molecular-targeted drug used as a first-line treatment for metastatic clear cell renal cell carcinoma (ccRCC); however, resistance to sunitinib has become a major problem in medical practice. Recently, bromodomain containing 4 (BRD4), a member of the bromodomain family proteins, was identified as a promising therapeutic target, and its inhibitor JQ1 has been shown to have inhibitory effects in various human cancers. However, the anti-cancer effects of JQ1 in ccRCC, particularly sunitinib-resistant ccRCC, are still unclear. Here, we aimed to elucidate the anti-cancer effects of JQ1 and the mechanisms underlying BRD4 inhibition in sunitinib-sensitive and -resistant ccRCCs. 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. Based on RNA sequencing analyses of ccRCC cells treated with JQ1 to elucidate the mechanisms other than MYC regulation, we identified several oncogenes that may be potential therapeutic targets or prognostic markers; patients with high expression of SCG5, SPOCD1, RGS19, and ARHGAP22 had poorer overall survival than those with low expression in TCGA ccRCC cohort. Chromatin immunoprecipitation assays revealed that these oncogenes may be promising BRD4 targets, particularly in sunitinib-resistant ccRCC cells. These results identified SCG5, SPOCD1, RGS19, and ARHGAP22 as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.
• Format (IMT): application/pdf
• Source: Diss_坂口大_ISK486_2018 （fulltext）; https://ir.kagoshima-u.ac.jp/record/14454/files/Diss_%E5%9D%82%E5%8F%A3%E5%A4%A7_ISK486_2018.pdf
• Access Restrictions: インターネット公開
• Related Material: Oncotarget; http://www.oncotarget.com/
• Related Material (DOI): 10.18632/oncotarget.25190
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 鹿児島大学 : 鹿児島大学リポジトリ