Mechanism of chemoresistance by HDAC1-associating protein and development of molecular targeted therapy

• Project/Area Number: 24650618
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Tumor biology
• Research Institution: Nagoya University
• Principal Investigator: TAKAHASHI Masahide 名古屋大学, 医学(系)研究科(研究院), 教授 (40183446)
• Co-Investigator(Kenkyū-buntansha): MURAKUMO Yoshiki 北里大学, 医学部, 教授 (40324438) ; KATO Takuya 名古屋大学, 医学系研究科, 助教 (00551970)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HDAC1 / RET finger protein / 抗がん剤耐性 / 卵巣がん / RFP / 神経膠芽腫 / ユビキチン化 / TRIM27

Research Abstract

Resistance to platinum- and taxane-based chemotherapy is a major cause of treatment failure in ovarian cancer. Thus, it is necessary to develop a predictive marker and molecular target for overcoming drug resistance in ovarian cancer treatment. Using an in vitro model, we previously found that the RET finger protein (RFP) which is known as HDAC-associating protein, confers cancer cell resistance to anticancer drugs. In this study, we showed that RFP was expressed in 62% of ovarian cancer patients and its positivity significantly correlated with drug resistance. Depletion of RFP by RNA interference in ovarian cancer cell lines, SKOV3 and HEY, significantly increased carboplatin- or paclitaxel-induced apoptosis and resulted in reduced anticancer drug resistance. In a nude mouse tumor xenograft model, inoculated RFP-knockdown ovarian cancer cells exhibited lower carboplatin resistance than control cells. These findings suggest that RFP could be a candidate for a molecular-targeted agent.

Research Products

• [Journal Article] TRIM27/MTRF-B-dependent integrin beta1 expression defines leading cells in cancer cell collecitives (2014)
  • Author(s): Kato, T., Enomoto, A., Watanabe, T., Haga, H., Ishida, S., Kondo, Y., Furukawa, K., Urano, T., Mii, S., Weng, L., Takagishi, M., Asai, M., Asai, N., Kaibuchi, K., Murakumo, Y. and Takahashi, M.
  • Journal Title: Cell Rep Volume: (in press)
• [Journal Article] Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells (2014)
  • Author(s): Niimi, K., Murakumo, Y., Watanabe, N., Kato, T., Mii, S., Enomoto, A., Asai, M., Asai, N., Yamamoto, E., Kajiyama, H., Shibata, K., Kikkawa, F., and Takahashi, M.
  • Journal Title: Cancer Sci Volume: 105 Pages: 545-552
• [Journal Article] TRIM27/MRTF-B-dependent integrinbeta1 expression defines leading cells in cancer cell collectives (2014)
  • Author(s): Takuya Kato Atsushi Enomoto, Takashi Watanabe, Hisashi Haga, Sumire Ishida, Yuji Kondo, Koichi Furukawa, Takeshi Urano, Shinji Mii, Liang Weng, Maki Takagishi, Masato Asai, Naoya Asai, Kozo Kaibuchi, Yoshiki Murakumo, Masahide Takahashi
  • Journal Title: Cell Reports Volume: ―
  • Peer Reviewed
• [Journal Article] Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells. (2014)
  • Author(s): Niimi K, Murakumo Y, Watanabe N, Kato T, Mii S, Enomoto A, Asai M, Asai N, Yamamoto E, Kajiyama H, Shibata K, Kikkawa F, Takahashi M.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 5 Pages: 545-52
  • DOI: 10.1111/cas.12390
  • Peer Reviewed / Open Access
• [Journal Article] The Rev7 subunit of DNA polymeraseζis essential for primordial germ cell maintenance in the mouse (2013)
  • Author(s): Watanabe, N., Mii, S., Asai, N., Asai, M., Niimi, K., Ushida, K., Kato, T., Enomoto, A., Ishii, H., Takahashi, M., and Murakumo, Y.
  • Journal Title: J. Biol. Chem Volume: 288 Pages: 10459-10471
• [Journal Article] Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer (2012)
  • Author(s): Horio, M., Kato, T., Mii, S., Enomoto, A., Asai, M., Asai, N., Murakumo, Y., Shibata, K., Kikkawa, F. and Takahashi, M.
  • Journal Title: Cancer Med Volume: 1 Pages: 218-229
• [Journal Article] RET finger protein expression is associated with prognosis in lung cancer with epidermal growth factor receptor mutations Pathol (2012)
  • Author(s): Iwakoshi, A., Murakumo, Y., Kato, T., Kitamura, A., Mii, S., Saito, S., Yatabe, Y. and Takahashi. M.
  • Journal Title: Int Volume: 62 Pages: 324-330
• [Journal Article] Ret finger protein inhibits muscle differentiation by modulating serum response factor and enhancer of polycomb 1 (2012)
  • Author(s): Kee, H. J., Kim, J-R, Joung, H., Choe, N., Lee, S. E., Eom, G. H., Kim, J. C., Geyer, S. H., Jijiwa, M., Kato, T., Kawai, K., Weninger, W. J., Seo, S. B., Nam, K-I., Jeong, M. H., Takahashi, M. and Kook, H.
  • Journal Title: Cell Death Differ Volume: 19 Pages: 121-131
• [Journal Article] RET finger protein expression is associated with prognosis in lung cancer with epidermal growth factor receptor mutations. (2012)
  • Author(s): Akari Iwakoshi
  • Journal Title: Pathol International Volume: 62 Issue: 5 Pages: 324-30
  • DOI: 10.1111/j.1440-1827.2012.02797.x
  • Peer Reviewed
• [Journal Article] Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer. (2012)
  • Author(s): Maiko Horio
  • Journal Title: Cancer Medicine Volume: 1 Issue: 2 Pages: 218-29
  • DOI: 10.1002/cam4.32
  • Peer Reviewed
• [Journal Article] Ret finger protein inhibits muscle differentiation by modulating serum response factor and enhancer of polycomb1 (2011)
  • Author(s): Hae Jin Kee
  • Journal Title: Cell Death & Differentiation Volume: 19 Issue: 1 Pages: 121-131
  • DOI: 10.1038/cdd.2011.72
  • Peer Reviewed
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis (2014)
  • Author(s): Takahashi, M., Enomoto, A. and Asai, N.
  • Organizer: International Symposium on Nanomedicine
  • Place of Presentation: Nagoya University, Nagoya
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis (2013)
  • Author(s): Takahashi, M., Enomoto, A. and Asai, N.
  • Organizer: Joint meeting of the Medical School of Nagoya University and the University of Adelaide
  • Place of Presentation: The University of Adelaide, Adelaide, Australia
  • Year and Date: 2013-05-27
• [Presentation] Regulatory mechanism of integrin beta1 expression in collectively migrating cancer cells (2013)
  • Author(s): Takuya Kato
  • Organizer: Ninth AACR-Japanese Cancer Association Joint Conference
  • Place of Presentation: Maui, HI, USA
• [Presentation] RET finger protein related to early cancer recurrence and potential therapeutic target in ovarian cancer (2012)
  • Author(s): Horio, M., Kato, T., Enomoto, A., Asai, N., Murakumo, Y., Shibata, K., Kikkawa, F. and Takahashi, M.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌、札幌市
• [Presentation] RET finger proteinの発現は卵巣癌早期再発と関連し治療標的として有用である。 (2012)
  • Author(s): 堀尾麻衣子
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌）
• [Presentation] 移動するがん細胞集団におけるintegrin beta1の発現制御機構 (2012)
  • Author(s): 加藤琢哉
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌）
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis
  • Author(s): Masahide Takahashi
  • Organizer: Joint meeting of the Medical School of Nagoya University and the University of Adelaide
  • Place of Presentation: Adelaide, Australia
  • Invited
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/patho2/