Elucidation of epigenome-mediated mechanism for growth supression in castration-resistant prostate cancer

• Project/Area Number: 15K21282
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology; Tumor biology
• Research Institution: Nagoya City University
• Principal Investigator: SATO Shinya 名古屋市立大学, 大学院医学研究科, 研究員 (30464564)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: HDAC阻害剤 / エピゲノム機構 / microRNA / アンドロゲン受容体 / ホルモン治療抵抗性前立腺癌 / heterogeneity / 網羅的増殖抑制メカニズム / 癌治療 / miRNA / エピゲノム制御 / 予後 / histone acetylation / prostate cancer / androgen receptor / HDAC inhibitor / hormone therapy

Outline of Final Research Achievements

Targeting androgen receptor (AR) is one of the effective approaches for treatment of prostate cancers. Histone deacetylase (HDAC) alters the epigenetic status of tumor-associated genes, including those for miRNAs, and affects the behavior of cancers. We examined the molecular effects of a HDAC inhibitor, OBP-801, on prostate cancers. Treatment with OBP-801 efficiently suppressed cell growth of prostate cancer lines, together with AR downregulation, regardless of their hormone sensitivity. Among the upregulated miRNAs after OBP-801 treatment in the cell lines, miR-320a, was the most closely associated with AR expression. An miR-320a mimic suppressed AR protein expression together with growth suppression. Our data demonstrated that OBP-801 effectively suppressed AR activity via upregulation of miR-320a, which resulted in tumor cell growth suppression of prostate cancers. OBP-801 may be a promising AR-targeting reagent in AR-positive prostate cancer regardless of androgen dependency.

Research Products

• [Journal Article] Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma (2018)
  • Author(s): Sakai, E., Nakayama, M., Oshima, H., Kouyama, Y., Niida, A., Fujii, S., Ochiai, A., Nakayama, K. I., Mimori, K., Suzuki, Y., Hong, C. P., Ock, C. Y., Kim, S. J. and Oshima, M.
  • Journal Title: Cancer Research Volume: in press Pages: 1283-1295
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] HDAC阻害剤OBP-801のmiRNA発現制御を介した前立腺癌の増殖抑制機構の解明 (2016)
  • Author(s): 佐藤慎哉、勝島啓佑、鈴木周五、内木綾、加藤寛之、早川将史、山下依子、久野壽也、近藤豊、高橋智
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター (宮城県仙台市)
• [Presentation] Histone deacetylase inhibition in prostate cancer triggers miR-320-mediated suppression of the androgen receptor (2016)
  • Author(s): Shinya Sato, Keisuke Katsushima, Keiko Shinjo, Akira Hatanaka, Fumiharu Ohka, Shugo Suzuki, Aya Naiki-Ito, Norihito Soga, Satoru Takahashi, and Yutaka Kondo
  • Organizer: 第13回病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル (兵庫県神戸市)
  • Year and Date: 2016-07-29
• [Presentation] Study of Growth Suppressive Effect of Histone Deacetylase Inhibitor OBP-801 in Prostate Cancer (2016)
  • Author(s): 佐藤慎哉、勝島啓佑、鈴木周五、内木綾、加藤寛之、早川将史、山下依子、久野壽也、近藤豊、髙橋智
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-14
• [Presentation] Inhibition of histone deacetylase induces miR-320-mediated androgen receptor suppression in prostate cancer (2016)
  • Author(s): Shinya Sato, Keisuke Katsushima, Keiko Shinjo, Satoru Takahashi, and Yutaka Kondo
  • Organizer: American Association for Cancer Research 107th Annual Meeting 2016
  • Place of Presentation: Ernest N. Morial Convention Center New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Remarks] OBP-801
  • URL: http://www.oncolys.com/jp/pipeline/obp-801.html