エピジェネティック制御因子ＨＤＡＣ８のＡＴＬ発がんにおける役割の解明

• Project/Area Number: 26461437
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kinki University
• Principal Investigator: 樋口 智紀 近畿大学, 医学部, 助教 (00448771)
• Co-Investigator(Kenkyū-buntansha): 義江 修 近畿大学, 医学部, 教授 (10166910)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Discontinued (Fiscal Year 2015)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: HDAC8 / ATL / SOX4 / エピジェネティック

Outline of Annual Research Achievements

近年、我々は成人T細胞白血病（ATL）で転写因子Fra-2が複数の癌遺伝子を発現誘導するカスケードが存在することを明らかにし(Nakayama et al., Oncogene 2008)、さらに、それらの遺伝子の1つである転写因子SOX4がヒストン脱アセチル化酵素HDAC8を発現誘導し、ATL細胞の増殖や生存能に関与していることも示した（Higuchi et al., Blood, 2013）。昨年度は、ATLの臨床検体でHDAC8が一貫して発現し、p21/Cip1などの複数のがん抑制遺伝子の発現抑制を促すことで腫瘍細胞の生存能に関与することを示唆した。また、HDAC8はCDK4、EIF1A、ICBP90/UHRF1、TCF19などの細胞増殖関連遺伝子の発現誘導にも関与することも明らかにし、ATLにおけるHDAC8の新たな機能の一端を示した。
本年度は、同定したHDAC8下流候補遺伝子のATL細胞の増殖能への役割とATLにおけるHDAC8の新規結合標的分子の探索について検討した。その結果、１）HDAC8強制発現細胞株においてその細胞増殖が促進された、２）ATL細胞株におけるsiRNAを用いたHDAC8下流候補遺伝子のノックダウン実験系より、その細胞増殖にはCDK4が関与していた、３）免疫沈降法とMALDI-TOF/MSを用いたHDAC8結合標的分子探索によって、HDAC8は複数のZnフィンガードメインを有するタンパクと結合することを明らかにした。これらのことから、ATLにおいてHDAC8は細胞生存能だけでなく細胞増殖能も促進し、これらに関わる遺伝子群の発現制御はHDAC8によるZnフィンガーファミリーの直接的な機能制御を行っている可能性が示された。

Research Products

• [Journal Article] C-C chemokine receptor type 4 antagonist Compound 22 ameliorates experimental autoimmune encephalomyelitis. (2016)
  • Author(s): Moriguchi K, Miyamoto K, Tanaka N, Ueno R, Nakayama T, Yoshie O, Kusunoki S.
  • Journal Title: J Neuroimmunol Volume: 291 Pages: 54-58
  • DOI: 10.1016/j.jneuroim.2015.12.011
  • Peer Reviewed
• [Journal Article] Galectin-3 Plays an Important Role in Innate Immunity to Gastric Infection by Helicobacter pylori. (2016)
  • Author(s): Park AM, Hagiwara S, Hsu DK, Liu FT, Yoshie O.
  • Journal Title: Infection and Immunity Volume: 84(4) Issue: 4 Pages: 1184-1193
  • DOI: 10.1128/iai.01299-15
  • Peer Reviewed
• [Journal Article] Heat Shock Protein 27 Plays a Pivotal Role in Myofibroblast Differentiation and in the Development of Bleomycin-Induced Pulmonary Fibrosis (2016)
  • Author(s): Park AM, Kanai K, Itoh T, Sato T, Tsukui T, Inagaki Y, Selman M, Matsushima K, Yoshie O.
  • Journal Title: Plos One Volume: 11 Issue: 2 Pages: e0148998-e0148998
  • DOI: 10.1371/journal.pone.0148998
  • Peer Reviewed / Open Access
• [Journal Article] Upregulated CCL28 expression in the nasal mucosa in experimental allergic rhinitis: Implication for CD4(+) memory T cell recruitment (2016)
  • Author(s): Nagakubo D, Yoshie O, Hirata T
  • Journal Title: Cellular Immunology Volume: 302 Pages: 58-62
  • DOI: 10.1016/j.cellimm.2016.02.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role of chemokine CX3CL1 in progression of multiple myeloma via CX3CR1 in bone microenvironments. (2015)
  • Author(s): Wada A, Ito A, Iitsuka H, Tsuneyama K, Miyazono T, Murakami J, Shibahara N, Sakurai H, Saiki I, Nakayama T, Yoshie O, Koizumi K, Sugiyama T.
  • Journal Title: Oncol Rep. Volume: 33 Issue: 6 Pages: 2935-2939
  • DOI: 10.3892/or.2015.3941
  • Peer Reviewed
• [Journal Article] Molecular analysis of loss of CCR4 expression during mogamulizumab monotherapy in an adult T cell leukemia/lymphoma patient. (2015)
  • Author(s): Taguchi M, Imaizumi Y, Sasaki D, Higuchi T, Tsuruda K, Hasegawa H, Taguchi J, Sawayama Y, Imanishi D, Hata T, Yanagihara K, Yoshie O, Miyazaki Y.
  • Journal Title: Annals of Hematology Volume: 94(4) Issue: 4 Pages: 693-695
  • DOI: 10.1007/s00277-014-2239-1
  • Peer Reviewed
• [Journal Article] CCR4 and its ligands: from bench to bedside (2015)
  • Author(s): Yoshie O, Matsushima K
  • Journal Title: International Immunology Volume: 27 Issue: 1 Pages: 11-20
  • DOI: 10.1093/intimm/dxu079
  • Peer Reviewed
• [Journal Article] Functional roles of evolutionary conserved motifs and residues in vertebrate chemokine receptors (2015)
  • Author(s): Nomiyama H, Yoshie O
  • Journal Title: Journal of Leukocyte Biology Volume: 97 Issue: 1 Pages: 39-47
  • DOI: 10.1189/jlb.2ru0614-290r
  • Peer Reviewed
• [Journal Article] Structural and agonist properties of XCL2, the other member of the C-chemokine subfamily. (2015)
  • Author(s): Fox JC, Nakayama T, Tyler RC, Sander TL, Yoshie O, Volkman BF.
  • Journal Title: Cytokine Volume: 71(2) Issue: 2 Pages: 302-311
  • DOI: 10.1016/j.cyto.2014.11.010
  • Peer Reviewed
• [Journal Article] Generation of colonic IgA-secreting cells in the cecal patch (2014)
  • Author(s): Masahata, K., Umemoto, E., Kayama, H., Kotani, M., Nakamura, S., Kurakawa, T., Kikuta, J., Gotoh, K., Motooka, D., Sato, S., Higuchi, T., Baba, Y., Kurosaki, T., Kinoshita, M., Shimada, Y., Kimura, T., Okumura, R., Takeda, A., Tajima, M., Yoshie, O., Fukuzawa, M., Kiyono, H., Fagarasan, S., Iida, T., Ishii, M., Takeda, K
  • Journal Title: Nature Comm Volume: 5 Issue: 1 Pages: 3704-3704
  • DOI: 10.1038/ncomms4704
  • Peer Reviewed / Open Access
• [Journal Article] CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages. (2014)
  • Author(s): Kee JY, Ito A, Hojo S, Hashimoto I, Igarashi Y, Tsuneyama K, Tsukada K, Irimura T, Shibahara N, Takasaki I, Inujima A, Nakayama T, Yoshie O, Sakurai H, Saiki I, Koizumi K.
  • Journal Title: BMC Cancer. Volume: 14 Issue: 1 Pages: 949-949
  • DOI: 10.1186/1471-2407-14-949
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High efficiency of photon-to-heat conversion with a 6-layered metal/dielectric film structure in the 250-1200 nm wavelength region. (2014)
  • Author(s): Liu MH, Hu ET, Yao Y, Zang KY, He N, Li J, Zheng YX, Wang SY, Yoshie O, Lee Y, Wang CZ, Lynch DW, Chen LY.
  • Journal Title: Optics Express Volume: 22 Suppl 7 Issue: S7 Pages: A1843-A1843
  • DOI: 10.1364/oe.22.0a1843
  • Peer Reviewed
• [Journal Article] A pleomorphic carcinoma of the lung producing multiple cytokines and forming a rapidly progressive mass-like opacity. (2014)
  • Author(s): Matsumoto M, Nakayama T, Inoue D, Takamatsu K, Itotani R, Ishitoko M, Suzuki S, Sakuramoto M, Yuba Y, Yoshie O, Takemura M, Fukui M.
  • Journal Title: BMC Cancer Volume: 14 Issue: 1 Pages: 588-588
  • DOI: 10.1186/1471-2407-14-588
  • Peer Reviewed
• [Presentation] CREB，NF-κBおよびTaxによって相乗的に活性化されたFOSB遺伝子発現は，結果的にHTLV-1感染細胞の生存能に関与する (2015)
  • Author(s): 樋口智紀，稗島州雄，中山隆志，義江修
  • Organizer: 第74回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] SOX4はHDAC8を発現誘導し、皮膚T細胞リンパ腫の細胞増殖に寄与する (2014)
  • Author(s): 樋口 智紀，中山 隆志，義江 修
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27