Identification and functional analysis of androgen-responsive ncRNAs in prostate cancer

• Project/Area Number: 23791049
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Endocrinology
• Research Institution: The University of Tokyo
• Principal Investigator: TAKAYAMA Kenichi 東京大学, 医学部附属病院, 特任臨床医 (50508075)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ncRNA / 前立腺癌 / アンドロゲン

Research Abstract

We have identified a long non-coding RNA, which is located at the antisense region ofCTBP1 (Carboxyl teiminal binding protein 1) and then named this transcript‘CTBP1-AS’. CTBP1-AS is induced by androgen treatment and represses CTBP1. Upregulation of CTBP1-AS in prostate cancer promotes hormone-dependent and castration-resistant tumor growth. In addition, we also demonstrated the interaction of CTBP1-AS with one of the epigenetic modifiers which has RNA-binding domains and then subsequent genome-wide regulation of gene expression. Interestingly, cell cycle regulators are significantly enriched in such regulated genes. Taken together, we demonstrated a novel hormone dependent cell cycle regulation mechanism and CTBP1-AS may be a therapeutic targets for hormone refractory prostate cancer.We also identified and analyzed the functions of androgen-regulated miRNAs. We found one of such miRNA promotes prostate cancer growth and is related with the anti-androgen, bicalutamide-resistant cell proliferation. We are going to perform experiments of xenograft model to show the mechanism of development of hormonerefractory prostate cancer.

Research Products

• [Journal Article] Androgen-responsive non-coding RNA CTBP1-AS promotes prostate cancer growth by epigenetic regulation. (2013)
  • Author(s): Takayama K
  • Journal Title: EMBO J Volume: in press
  • Peer Reviewed
• [Journal Article] Clinical significance of amyloid precursor protein in patients with testicular germ cell tumor. (2013)
  • Author(s): Yamada Y, Fujimura T, Takahashi S, Takayama K, Urano T, Murata T, Obinata D, Ouchi Y, Homma Y, Inoue S
  • Journal Title: Adv Urol Volume: 2013 Pages: 348438-348438
  • DOI: 10.1155/2013/348438
  • Peer Reviewed
• [Journal Article] Transcriptional network of androgen receptor in prostate cancer progression. (2013)
  • Author(s): Takayama K
  • Journal Title: Int J Urol Volume: in press
  • NAID: 10031190533
  • Peer Reviewed
• [Journal Article] TACC2 is an androgen-responsive cell cycle regulator promoting androgen-mediated and castration-resistant growth of prostate cancer (2012)
  • Author(s): Takayama K, Horie-Inoue K, Suzuki T, Urano T, Ikeda K, Fujimura T, Takahashi S, Homma Y, Ouchi Y, Inoue S
  • Journal Title: Mol Endocrinol Volume: 26 Pages: 748-761
• [Journal Article] Inoue S: 14-3-3-, a novel androgen-responsive gene, is upregulated in prostate cancer and promotes prostate cancer cell proliferation and survival (2012)
  • Author(s): Murata T, Takayama K, Urano T, Fujimura T, Ashikari D, Obinata D, Horie-Inoue K, Takahashi S, Ouchi Y, Homma Y
  • Journal Title: Clin Cancer Res Volume: 18 Pages: 5617-5627
• [Journal Article] Inoue S: Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer (2012)
  • Author(s): Obinata D, Takayama K, Urano T, Murata T, Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K, Homma Y, Ouchi Y, Takahashi S
  • Journal Title: Int J Cancer Volume: 130 Pages: 1021-1028
• [Journal Article] Inoue S: Clinical significance of steroid and xenobiotic receptor (SXR) and its targeted gene CYP3A4 in human prostate cancer (2012)
  • Author(s): Fujimura T, Takahashi S, Urano T, Tanaka T, Zhang W, Azuma K, Takayama K, Obinata D, Murata T, Horie-Inoue K, Kodama T, Ouchi Y, Homma Y
  • Journal Title: Cancer Sci Volume: 103 Pages: 176-180
• [Journal Article] Inoue S: ARFGAP3, an androgen target gene, promotes prostate cancer cell proliferation and migration (2012)
  • Author(s): Obinata D, Takayama K, Urano T, Murata T, Ikeda K, Horie-Inoue K, Ouchi Y,Takahashi S
  • Journal Title: Int J Cancer Volume: 130 Pages: 2240-2248
• [Journal Article] TACC2 is an androgen-responsive cell cycle regulator promoting androgen-mediated and castration-resistant growth of prostate cancer (2012)
  • Author(s): Takayama K, Horie-Inoue K, Suzuki T, Urano T, Ikeda K, Fujimura T, Takahashi S, Homma Y, Ouchi Y, Inoue S
  • Journal Title: Mol Endocrinol Volume: (in press) Issue: 5 Pages: 748-761
  • DOI: 10.1210/me.2011-1242
  • Peer Reviewed
• [Journal Article] ARFGAP3, an androgen target gene, promotes prostate cancer cell proliferation and migration (2012)
  • Author(s): Obinata D, Takayama K, Urano T, Murata T, Ikeda K, Horie-Inoue K, Ouchi Y, Takahashi S, Inoue S
  • Journal Title: Int J Cancer Volume: 130 Issue: 10 Pages: 2240-2248
  • DOI: 10.1002/ijc.26224
  • NAID: 10031156601
  • Peer Reviewed
• [Journal Article] 14-3-3zeta, a novel androgen-responsive gene, is upregulated in prostate cancer and promotes prostate cancer cell proliferation and survival. (2012)
  • Author(s): Murata T
  • Journal Title: Clin Cancer Res Volume: 18 Issue: 20 Pages: 5617-5627
  • DOI: 10.1158/1078-0432.ccr-12-0281
  • Peer Reviewed
• [Journal Article] Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer (2012)
  • Author(s): Obinata D, Takayama K, Urano T, Murata T, Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K, Homma Y, Ouchi Y, Takahashi S, Inoue S
  • Journal Title: Int J Cancer Volume: 130 Issue: 5 Pages: 1021-1028
  • DOI: 10.1002/ijc.26043
  • Peer Reviewed
• [Journal Article] Clinical significance of steroid and xenobiotic receptor(SXR) and its targeted gene CYP3A4 in human prostate cancer (2012)
  • Author(s): Fujimura T, Takahashi S, Urano T, Tanaka T, Zhang W, Azuma K, Takayama K, Obinata D, Murata T, Horie-Inoue K, Kodama T, Ouchi Y, Homma Y, Inoue S
  • Journal Title: Cancer Sci Volume: 103 Issue: 2 Pages: 176-180
  • DOI: 10.1111/j.1349-7006.2011.02143.x
  • Peer Reviewed
• [Journal Article] TACC2 is an androgen-responsive cell cycle regulator promoting androgen-mediated and castration-resistant growth of prostate cancer. (2012)
  • Author(s): Takayama K, Horie-Inoue K, Suzuki T, Urano T, Ikeda K, Fujimura T, Takahashi S, Homma Y, Ouchi Y, Inoue S
  • Journal Title: Mol Endocrinol Volume: in press
  • Peer Reviewed
• [Journal Article] Androgen-responsive non-coding RNA CTBP1-AS promotes prostate cancer growth by epigenetic regulation.
  • Author(s): Takayama K, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K, Urano T, Fujimura T, Takagi K, Takahashi S, Homma Y, Ouchi Y, Aburatani H, Hayashizaki Y, Inoue S
  • Journal Title: EMBO J Volume: (in press)
• [Journal Article] Clinical significance of amyloid precursor protein in patients with testicular germ cell tumor
  • Author(s): Yamada Y, Fujimura T, Takahashi S, Takayama K, Urano T, Murata T, Obinata D, Ouchi Y, Homma Y, Inoue S
  • Journal Title: Adv Urol Volume: (in press)
• [Journal Article] Transcriptional network of androgen receptor in prostate cancer progression
  • Author(s): Takayama K, Inoue S
  • Journal Title: Int J Urol Volume: (in press)
  • NAID: 10031190533
• [Presentation] ゲノムワイドのアンドロゲン受容体結合部位解析により同定された新規アンドロゲン受容体標的遺伝子の発現制御機構の解析 (2013)
  • Author(s): 芦苅大作、高山賢一、浦野友彦、大日方大亮、高橋悟、井上聡
  • Organizer: 第22回泌尿器科分子・細胞研究会
  • Place of Presentation: 高知
• [Presentation] 前立腺癌細胞におけるアンドロゲン応答性Non-coding RNAの同定ならびに機能解析 (2013)
  • Author(s): 高山賢一、堀江公仁子、池田和博、浦野友彦、大内尉義、井上聡
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] シンポジウム]前立腺がんにおけるゲノムワイドでのAR標的遺伝子の同定 (2012)
  • Author(s): 高山賢一
  • Organizer: 第12回関東ホルモンと癌研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-01-21
• [Presentation] 次世代シーケンサーを用いた前立腺がん細胞株におけるmiRNAの発現解析 (2012)
  • Author(s): 三沢彩、高山賢一、浦野友彦、井上聡
  • Organizer: 第12回関東ホルモンと癌研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-01-21
• [Presentation] アンドロゲン応答性フォークヘッド転写因子FOXP1の全ゲノムにおける結合部位同定によるARシグナル調節機構の解析 (2012)
  • Author(s): 高山賢一、岡部篤史、堤修一、浦野友彦、堀江公仁子、池田和博、大内尉義、油谷浩幸、井上聡
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Inoue S: Short RNA sequence analysis for androgen responsive miRNA expression profile in prostate cancer cell lines(前立腺癌細胞におけるアンドロゲン応答性miRNA同定を目的とした Short RNA シークエンス解析) (2012)
  • Author(s): Takayama K, Misawa A, Urano T, Horie-Inoue K, Mano H, Ouchi Y
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: 札幌
• [Presentation] TMPRSS2-ERG 融合遺伝子発現を標的と したピロール・イミダゾール(PI)ポリアミ ドは前立腺癌細胞の増殖を抑制させる(Pyrrole-imidazole (PI) polyamide targeting of TMPRSS2-ERG gene fusion repress prostate cancer cell progression.) (2012)
  • Author(s): 大日方大亮、藤原恭子、高山賢一、浦野友彦、永瀬浩喜、井上聡、高橋悟
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: 札幌
• [Presentation] ホルモン療法抵抗性前立腺がん細胞におけるエネルギー代謝関連核内受容体作用の検討 (2012)
  • Author(s): 堀江公仁子、高山賢一、伊地知暢宏、池田和博、井上聡
  • Organizer: 脳心血管抗加齢研究会2012
  • Place of Presentation: 大阪
• [Presentation] 次世代シーク エンサーを用いたホルモン療法抵抗性前立腺癌への進展におけるアンドロゲン受容体シグナルの統合的解析( Global analysis of androgen receptor signaling in the prostate cancer progression to castration-resistance by next generation sequencers) (2012)
  • Author(s): 高山賢一、堀江公仁子、池田和博、浦野 友彦、大内尉義、井上聡
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] 前立腺癌細胞における新規アンドロゲン応答遺伝子G3BP2の同定及び機能解析 (2012)
  • Author(s): 芦苅大作、高山賢一、浦野友彦、大日方大亮、高橋悟、井上聡
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] 前立腺癌細胞におけるアンドロゲン応答性miRNA同定を目的としたShort RNAシークエンス解析 (2012)
  • Author(s): 高山賢一
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: 札幌
• [Presentation] TMPRSS2-ERG融合遺伝子発現を標的としたピロール・イミダゾール(PI)ポリアミドは前立腺癌細胞の増殖を抑制させる (2012)
  • Author(s): 大日方大亮
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Genome-wide identification of estrogen responsive genes in breast cancer MCF-7 cells using cap analysis of gene expression. (2012)
  • Author(s): 池田和博
  • Organizer: 生命医薬情報学連合大会 (2012年日本バイオインフォマティクス学会年会、情報計算化学生物学会（CBI学会）年次大会、オミックス医療研究会年会
  • Place of Presentation: 東京
• [Presentation] 次世代シークエンサーを用いたホルモン療法抵抗性前立腺癌への進展におけるアンドロゲン受容体シグナルの統合的解析 (2012)
  • Author(s): 高山賢一
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Inoue S: OCT1 coordinately regulates and rogen receptor and is aprognostic factor for prostate cancer (2011)
  • Author(s): Obinata D, Takayama K, Urano T, Murata T, Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K, Homma Y, Ouchi Y, Takahashi S
  • Organizer: 第99回日本泌尿器科学会【スキルアップ企画】 日本泌尿器科学会国際学会フォーラム: 国際学会のための医学英語
  • Year and Date: 2011-04-22
• [Presentation] 前立腺癌細胞における新規アンドロゲン応答遺伝子TACC2の細胞周期、細胞増殖における機能解析 (2011)
  • Author(s): 高山賢一、堀江公仁子、池田和博、浦野友彦、大内尉義、井上聡
  • Organizer: 第84回日本内分泌学会学術総会
  • Place of Presentation: 神戸
• [Presentation] アンドロゲン依存性増殖にかかわるアンドロゲン応答性マイクロRNAの次世代シーケンサーによる包括的同定とその新しい機能の解明 (2011)
  • Author(s): 村田太郎、高山賢一、浦野友彦、藤村哲也、堀江公仁子、池田和博、高橋悟、大内尉義、本間之夫、井上聡
  • Organizer: 第99回日本泌尿器科学会総会
  • Place of Presentation: 名古屋
• [Presentation] 前立腺癌におけるAR転写調節因子であるOCT1の役割 (2011)
  • Author(s): 大日方大亮、高山賢一、浦野友彦、堀江公仁子、池田和博、大内尉義、高橋悟、井上聡
  • Organizer: 第99回日本泌尿器科学会総会
  • Place of Presentation: 名古屋
• [Presentation] 次世代シークエンサーによるアンドロゲン受容体結合部位および標的遺伝子のエピジェネティックな発現制御機構の解析 (2011)
  • Author(s): 高山賢一、堤修一、堀江公仁子、池田和博、浦野友彦、大内尉義、油谷浩幸、井上聡
  • Organizer: 第30回アンドロロジー学会学術大会
  • Place of Presentation: 東京
• [Presentation] Inoue S: TACC2 is an androgen-regulated cell cycle regulator that mediates castration-resistant growth of prostate cancer (2011)
  • Author(s): Takayama K, Horie-Inoue K, Suzuki T, Urano T, Ikeda K, Fujimura T, Takahashi S, Homma Y, Ouchi Y
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Inoue S: Oct1 positively regulates the androgen-upregulated gene ACSL3, a5'-translocation partner of ETV1, with androgen receptor in human prostate cancer (2011)
  • Author(s): Obinata D, Takayama K, Urano T, Takahashi S
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 前立腺癌細胞における新規アンドロゲン応答遺伝子TACC2の細胞周期、細胞増殖における機能解析 (2011)
  • Author(s): 高山賢一、堀江公仁子、池田和博、浦野友彦、大内尉義、井上聡
  • Organizer: 第84回日本内分泌学会学術総会
  • Place of Presentation: 兵庫
• [Presentation] アンドロゲン依存性増殖にかかわるアンドロゲン応答性マイクロRNAの次世代シーケンサーによる包括的同定とその新しい機能の解明 (2011)
  • Author(s): 村田太郎、高山賢一、浦野友彦、藤村哲也、堀江公仁子、池田和博、高橋悟、大内尉義、本間之夫、井上聡
  • Organizer: 第99回日本泌尿器科学会総会
  • Place of Presentation: 愛知
• [Presentation] 前立腺癌におけるAR転写調節因子であるOCT1の役割 (2011)
  • Author(s): 大日方大亮、高山賢一、浦野友彦、堀江公仁子、池田和博、大内尉義、高橋悟、井上聡：
  • Organizer: 第99回日本泌尿器科学会総会
  • Place of Presentation: 愛知
• [Presentation] TACC2 is an androgen-regulated cell cycle regulator that mediates castration-resistant growth of prostate cancer. (2011)
  • Author(s): Takayama K, Horie-Inoue K, Suzuki T, Urano T, Ikeda K, Fujimura T, Takahashi S, Homma Y, Ouchi Y, Inoue S
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知
• [Presentation] Oct1 positively regulates the androgen-upregulated gene ACSL3, a 5’-translocation partner of ETV1, with androgen receptor in human prostate cancer. (2011)
  • Author(s): Obinata D, Takayama K, Urano T, Takahashi S, Inoue S
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知
• [Presentation] 14-3-3zita is an androgen-regulated gene that activates the andorogen receptor signalingand promotes prostate cancer. (2011)
  • Author(s): Murata T, Takayama K, Urano T, Fujimura T, Horie-Inoue K, Ikeda K, Takahashi S, Ouchi Y, Homma Y, Inoue S
  • Organizer: 2011 Annual Meeting, American Urological Association
  • Place of Presentation: Washington DC, USA
• [Presentation] OCT1 coordinately regulates androgen receptor and is a prognostic factor for prostate cancer. (2011)
  • Author(s): Obinata D, Takayama K, Urano T, Murata T, Kumagai J, Fujimura T, Ikeda K, Horie K, Takahashi S, Inoue S
  • Organizer: 2011 Annual Meeting, American Urological Association
  • Place of Presentation: Washington DC, USA
• [Presentation] Identification of androgen-regulated cytochrome c oxidase-related genes in hormone-sensitive prostate cancer cells through RNA-sequencing and systemic chromatin immunoprecipitation analysis. (2011)
  • Author(s): Horie-Inoue K, Takayama K, Ikeda K, Suzuki Y, Inoue S
  • Organizer: Mitochondrial Assembly & Dynamics in Health, Disease & Aging, FASEB Summer Research Conferences
  • Place of Presentation: Steamboat Springs, Colorado, USA
• [Presentation] Next generation sequencing identifies androgen-regulated mitochondrial respiratory genes in prostate cancer cells. (2011)
  • Author(s): Horie-Inoue K, Takayama K, Ikeda K, Inoue S
  • Organizer: Translation of the Cancer Genome: Scientific, Clinical, and Operational Challenges, AACR
  • Place of Presentation: San Francisco, CA, USA
• [Book] MicroRNAs in Prostate Cancer, microRNAs in cancer (2012)
  • Author(s): Misawa A
  • Publisher: Science Publishers
• [Book] British Channel Islands
  • Author(s): Misawa A, Takayama K
  • Publisher: Science Publishers, Jersey