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

2019 Fiscal Year Final Research Report

• 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
• Keywords: 血液腫瘍学 / 腫瘍メタボリズム

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.

Free Research Field

血液内科学

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。