Identification of the enhancer sequences that are controlled by androgen receptor

• Project/Area Number: 20K09539
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Kyoto University
• Principal Investigator: Fujita Jun 京都大学, 医学研究科, 客員研究員 (50173430)
• Co-Investigator(Kenkyū-buntansha): 赤松 秀輔 京都大学, 医学研究科, 准教授 (20767248) ; 武田 俊一 京都大学, 医学研究科, 名誉教授 (60188191)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2021: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2020: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 前立腺癌 / アンドロゲン / エンハンサー / エンハンサーRNA / ホルモン治療抵抗性 / LNCap / トランスクリプトーム / c-MYC

Outline of Research at the Start

本研究は、アンドロゲンで活性化される転写制御領域（エンハンサー配列）を前立腺癌細胞株（LNCap）において新規に5,000以上見つける。見つけたエンハンサー配列を公開ビッグデータと照合し、(1) 細胞増殖に関与する配列をリストアップ；(2) (1)の配列の中にある前立腺癌体細胞変異を全部同定；(3) (2)の中で発癌や去勢抵抗性の原因になりそうな変異の候補を全部リストアップする。(3)の変異の影響を、アンドロゲン依存的に増殖するLNCapを使い、解析する。以上の実験から、アンドロゲン依存的細胞増殖に関与するエンハンサーを同定し、その中にある、去勢抵抗性の原因になる変異を決定する。

Outline of Final Research Achievements

We identified more than 2,000 enhancers that eRNA expression was induced by androgen addition. Half of them are newly found (novel enhancers). Differences between known androgen-dependent enhancers and novel enhancers in terms of colocalization with epigenetic markers, androgen receptor binding sites, and FOXA1 transcription factor binding sites We conclude that the novel enhancer is also truly androgen dependent.

Academic Significance and Societal Importance of the Research Achievements

各遺伝子に対して、数個以上のエンハンサーがその発現を制御すると考えられているが、実際にどれだけの数のエンハンサーが存在するか不明である。特に、ホルモンなどの外的刺激によって一過性に活性化されるエンハンサーは不明である。学術的意義は、2,000箇所以上のアンドロゲンによって活性化されるエンハンサーの同定である。社会的意義は、この同定が前立腺癌のホルモン治療抵抗性の機序の解明へ貢献できることである。

Research Products

• [Int'l Joint Research] Cedars-Sinai Medical Center/Memorial Sloan Kettering Cancer Center(米国)
• [Int'l Joint Research] Shenzhen University(中国)
• [Int'l Joint Research] University of Bern(スイス)
• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] University of British Columbia/BC Cancer Agency(カナダ)
• [Int'l Joint Research] アンダルシア分子生物学・再生医学センター(スペイン)
• [Journal Article] ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen (2023)
  • Author(s): Najnin Rifat Ara、Al Mahmud Md Rasel、Rahman Md Maminur、Takeda Shunichi、Sasanuma Hiroyuki、Tanaka Hisashi、Murakawa Yasuhiro、Shimizu Naoto、Akter Salma、Takagi Masatoshi、Sunada Takuro、Akamatsu Shusuke、He Gang、Itou Junji、Toi Masakazu、Miyaji Mary、Tsutsui Kimiko M.、Keeney Scott、Yamada Shintaro
  • Journal Title: Cell Reports Volume: 42 Issue: 1 Pages: 111909-111909
  • DOI: 10.1016/j.celrep.2022.111909
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks (2022)
  • Author(s): Akter Salma、Shimba Akihiro、Ikuta Koichi、Mahmud Md. Rasel Al、Yamada Shintaro、Sasanuma Hiroyuki、Tsuda Masataka、Sone Masakatsu、Ago Yukio、Murai Kenichi、Tanaka Hisashi、Takeda Shunichi
  • Journal Title: Genes to Cells Volume: 28 Issue: 1 Pages: 53-67
  • DOI: 10.1111/gtc.12993
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• [Journal Article] Development and validation of prediction model for incident overactive bladder: The Nagahama study (2022)
  • Author(s): Funada Satoshi、Luo Yan、Yoshioka Takashi、Setoh Kazuya、Tabara Yasuharu、Negoro Hiromitsu、Yoshimura Koji、Matsuda Fumihiko、Efthimiou Orestis、Ogawa Osamu、Furukawa Toshi A、Kobayashi Takashi、Akamatsu Shusuke
  • Journal Title: International Journal of Urology Volume: 29 Issue: 7 Pages: 748-756
  • DOI: 10.1111/iju.14887
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of <scp>IDC‐P</scp> as predictive factor after intensity‐modulated radiation therapy (2022)
  • Author(s): Aizawa Rihito、Tsuzuki Toyonori、Haga Hironori、Nakamura Kiyonao、Ogata Takashi、Inoue Takahiro、Kobayashi Takashi、Akamatsu Shusuke、Goto Takayuki、Ogawa Osamu、Mizowaki Takashi
  • Journal Title: Cancer Science Volume: 113 Issue: 7 Pages: 2425-2433
  • DOI: 10.1111/cas.15392
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Utility of Germline Genetic Testing in Japanese Men Undergoing Prostate Biopsy (2022)
  • Author(s): Akamatsu Shusuke, Terada Naoki, Takata Ryo、...、Yamamoto Michio、...、Ogawa Osamu
  • Journal Title: JNCI Cancer Spectrum Volume: 6 Issue: 1
  • DOI: 10.1093/jncics/pkac001
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer (2022)
  • Author(s): Kimura H、Mizuno K、Shiota M、Narita S、Terada N、Fujimoto N、Ogura K、Hatano S、Iwasaki Y、Hakozaki N、Ishitoya S、Sumiyoshi T、Goto T、Kobayashi T、Nakagawa H、Kamoto T、Eto M、Habuchi T、Ogawa O、Momozawa Y、Akamatsu S
  • Journal Title: British Journal of Cancer Volume: 127 Issue: 9 Pages: 1680-1690
  • DOI: 10.1038/s41416-022-01915-2
  • Peer Reviewed
• [Journal Article] A case of microsatellite instability-high clinically advanced castration-resistant prostate cancer showing a remarkable response to pembrolizumab sustained over at least 18 months (2022)
  • Author(s): Shimizu Kosuke、Sano Takeshi、Mizuno Kei、Sunada Takuro、Makita Noriyuki、Hagimoto Hiroki、Goto Takayuki、Sawada Atsuro、Fujimoto Masakazu、Ichioka Kentaro、Ogawa Osamu、Kobayashi Takashi、Akamatsu Shusuke
  • Journal Title: Molecular Case Studies Volume: 8 Issue: 4 Pages: a006194-a006194
  • DOI: 10.1101/mcs.a006194
  • Peer Reviewed / Open Access
• [Journal Article] Mammalian cold-inducible RNA-binding protein facilitates wound healing through activation of AMP-activated protein kinase. (2020)
  • Author(s): Higashitsuji H, Fujita T, Higashitsuji H, Fujita J.
  • Journal Title: Biochem Biophys Res Commun. Volume: 533 Issue: 4 Pages: 1191-1197
  • DOI: 10.1016/j.bbrc.2020.10.004
  • Peer Reviewed / Open Access
• [Journal Article] TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands. (2020)
  • Author(s): Mahmud MRA, Ishii K, Lozano CB, Sainz ID, Toi M, Akamatsu S, Fukumoto M, Watanabe M, Takeda S, Ledesma FC, Sasanuma H.
  • Journal Title: Genes to Cells Volume: in press Issue: 7 Pages: 450-465
  • DOI: 10.1111/gtc.12770
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CDK12 KOとTP53 KDの組み合わせでは臨床のCDK12 LOF前立腺癌にみられる高悪性度を模倣しない (2021)
  • Author(s): 上山裕樹、福井智洋、砂田拓郎、木村博子、後藤崇之、小林恭、赤松秀輔
  • Organizer: 第80回日本癌学会学術総会