Roles of HDAC1/3 effecting on metabolic shift in myeloma cells; Development of a novel treatment strategy targeting metabolic shift

• Project/Area Number: 18K16118
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokushima
• Principal Investigator: HARADA Takeshi 徳島大学, 病院, 特任助教 (10618359)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 血液腫瘍学 / 腫瘍メタボリズム / HDAC / Cancer metabolism

Outline of Final Research Achievements

We here investigated the biological significance of class-I histone deacetylases (HDACs), especially HDAC1 and HDAC3 in multiple myeloma (MM). We first revealed the downregulation of IRF4 and PIM2, which are the master transcription factor and the regulator of tumor metabolism, respectively, in the HDAC1-knockdown MM cells compared to control cells or HDAC3-knockdown cells. In addition, we delineated the mechanisms of constitutively high expression of PIM2 by the intrinsic HDAC1-IRF4 axis in MM cells. Furthermore, PIM2 was upregulated by the extrinsic myeloma-related microenvironmental factor such as IL-6. Finally, we developed the novel treatment strategy of combination of class-I HDAC inhibitor MS-275 with the PIM inhibitor SMI-16a in vitro and in vivo analysis. Taken together, our findings suggested that MM cell metabolism is regulated by PIM2, which are governed by the HDAC1-IRF4 intrinsic pathway and the myeloma niche-related extrinsic one.

Academic Significance and Societal Importance of the Research Achievements

HDACは遺伝子発現抑制に働くエピゲノム因子として知られているが、骨髄腫細胞では、HDAC1が高発現しているにも関わらず、腫瘍では種々の遺伝子が高発現している。本研究では、骨髄腫細胞でHDAC1によるIRF4およびPIM2の発現維持機構の一端を解明し、HDAC1による遺伝子発現制御に関する新たな知見を提唱した点に学術的意義がある。また、骨髄腫に対するクラスI HDACとPIMを標的とする併用療法の開発を行い、HDACアイソフォームの役割を明らかにしながらメタボリックシフトを標的とする治療法の開発に繋げた本研究は、他の悪性疾患にも応用可能な研究であり、社会的意義を有すると考えられる。

Research Products

• [Journal Article] PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ. (2019)
  • Author(s): Iwasa Masami、Harada Takeshi、Oda Asuka、Bat-Erdene Ariunzaya、Teramachi Jumpei、Tenshin Hirofumi、Ashtar Mohannad、Oura Masahiro、Sogabe Kimiko、Udaka Kengo、Fujii Shiro、Nakamura Shingen、Miki Hirokazu、Kagawa Kumiko、Ozaki Shuji、Abe Masahiro
  • Journal Title: Oncotarget Volume: 10 Issue: 20 Pages: 1903-1917
  • DOI: 10.18632/oncotarget.26726
  • Peer Reviewed / Open Access
• [Journal Article] Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling (2019)
  • Author(s): Ho Matthew、Chen Tianzeng、Liu Jiye、Dowling Paul、Hideshima Teru、Zhang Li、Morelli Eugenio、Camci-Unal Gulden、Wu Xinchen、Tai Yu-Tzu、Wen Kenneth、Samur Mehmet、Schlossman Robert L.、Mazitschek Ralph、Kavanagh Emma L.、Lindsay Sinead、Harada Takeshi、McCann Amanda、Anderson Kenneth C.、O’Gorman Peter、Bianchi Giada
  • Journal Title: Leukemia Volume: 34 Issue: 1 Pages: 196-209
  • DOI: 10.1038/s41375-019-0493-x
  • NAID: 120006999404
  • Peer Reviewed
• [Journal Article] Class 1 HDAC and HDAC6 inhibition inversely regulates CD38 induction in myeloma cells via interferon-α and ATRA (2018)
  • Author(s): Bat-Erdene Ariunzaya、Nakamura Shingen、Oda Asuka、Iwasa Masami、Teramachi Jumpei、Ashtar Mohannad、Harada Takeshi、Miki Hirokazu、Tenshin Hirofumi、Hiasa Masahiro、Fujii Shiro、Sogabe Kimiko、Oura Masahiro、Udaka Kengo、Kagawa Kumiko、Yoshida Sumiko、Aihara Ken-ichi、Kurahashi Kiyoe、Endo Itsuro、Abe Masahiro
  • Journal Title: British Journal of Haematology Volume: 印刷中 Issue: 5 Pages: 969-974
  • DOI: 10.1111/bjh.15673
  • Peer Reviewed / Open Access
• [Presentation] The novel therapeutic strategy targeting the HDAC1-IRF4-PIM2 pathway in myeloma cells. (2019)
  • Author(s): Harada T, Oda A, Tenshin H, Teramachi J, Oura M, Sogabe K, Iwasa M, Fujii S, Nakamura S, Miki H, Kagawa K, Hideshima T, Anderson KC, Abe M.
  • Organizer: The 44rd Annual Meeting of the Japanese Society of Myeloma
• [Presentation] Targeting myeloma metabolisoms regulated by HDAC1-IRF4 axis can be a novel therapeutic strategy. (2019)
  • Author(s): Harada T, Oda A, Tenshin H, Teramachi J, Oura M, Sogabe K, Fujii S, Nakamura S, Miki H, Kagawa K, Ozaki S, Hideshima T, Anderson KC, Abe M.
  • Organizer: The 17th International Myeloma Workshop
• [Presentation] 多発性骨髄腫におけるHDACアイソフォームの役割とその選択的阻害による治療法の開発 (2019)
  • Author(s): 原田武志
  • Organizer: 第81回日本血液学会学術集会
  • Invited
• [Presentation] Novel therapeutic rationale for targeting HDAC1 and PIM2 in multiple myeloma. (2019)
  • Author(s): Harada T, Oda A, Ohguchi H, Grondin Y, Tenshin H, Hiasa M, Teramachi J, Oura M, Sogabe K, Fujii S, Nakamura S, Miki H, Kagawa K, Ozaki S, Hideshima T, Anderson KC, Abe M.
  • Organizer: The 61th Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] HDAC1/3 inhibition disrupts the IRF4-Pim-2 pathway to induce effective myeloma cell death (2018)
  • Author(s): Harada T, Oda A, Teramachi J, Bat-Erdene A, Iwasa M, Maeda Y, Nakamura S, Oura M, Fujii S, Miki H, Kagawa K, Hideshima T, Anderson KC, Abe M
  • Organizer: The 43rd Annual Meeting of the Japanese Society of Myeloma
• [Presentation] Selective inhibition of class-I HDAC induces myeloma cell death through targeting IRF4-Pim-2 axis (2018)
  • Author(s): Harada T, Oda A, Teramachi J, Bat-Erdene A, Iwasa M, Oura M, Nakamura S, Kagawa K, Okamoto Y, Sogabe K, Fujii S, Miki H, Ozaki S, Hideshima T, Anderson KC, Abe M
  • Organizer: The 9th JSH International Symposium 2018 in Kyoto
• [Presentation] Roles of HDAC1 and HDAC3 as therapeutic targets against myeloma cells (2018)
  • Author(s): Harada T
  • Organizer: The 80th Annual Meeting of the Japanese Society of Hematology
  • Invited
• [Presentation] The critical role of the HDAC1-IRF4-Pim-2 axis in myeloma cell growth and survival: therapeutic impacts of targeting the HDAC1-IRF4-Pim-2 axis (2018)
  • Author(s): Harada T, Oda A, Grondin Y, Teramachi J, Bat-Erdene A, Iwasa M, Oura M, Nakamura S, Kagawa K, Okamoto Y, Sogabe K, Fujii S, Miki H, Ozaki S, Hideshima T, Anderson KC, Abe M
  • Organizer: The 60th ASH Annual Meeting & Exposition
  • Int'l Joint Research