Analysis of anti-tumor mechanism underlying inhibition of a histone methyltransferase DOT1L

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03518
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Suzuki Hiromu 札幌医科大学, 医学部, 教授 (20381254)
• Co-Investigator(Kenkyū-buntansha): 高澤 啓 札幌医科大学, 医学部, 准教授 (00593021) ; 仲瀬 裕志 札幌医科大学, 医学部, 教授 (60362498)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: DOT1L / ヒストン修飾 / エピゲノム / 多発性骨髄腫 / 乳がん

Outline of Final Research Achievements

DOT1L is the only known histone methyltransferase that catalyzes mono-, di- and trimethylation at H3K79. We have previously shown that DOT1L is required for multiple myeloma cell survival. In this study, we evaluated the antitumor effect of DOT1Li in various human malignancies. Treatment with DOT1L inhibitors suppressed proliferation of ER+ breast cancer cells as well as HER2+ cells. Transcriptome analysis showed that genes associated with cell cycle and MYC signaling were suppressed while those related to immune system and interferon (IFN) signaling were strongly upregulated by DOT1L inhibition. ChIP-seq analysis revealed that DOT1L inhibition upregulated active histone marks, H3K4me3 and H3K27ac, in a number of genomic regions, including repetitive elements. Our data suggest that DOT1L inhibition exerts anti-tumor effects by activating interferon signaling in breast cancer cells.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

エピジェネティックな修飾は、その可塑性から有望な治療標的と考えられている。我々はDOT1L阻害が、多発性骨髄腫や乳がんに対し高い抗腫瘍効果を示すことを明らかにした。DOT1Lの阻害は、MYCやERBB2などのがん遺伝子の転写抑制に働くことから、抗腫瘍効果につながると考えられた。さらに我々は、DOT1L阻害がインターフェロンシグナルや免疫応答関連遺伝子を活性化すること、そして内在性レトロウイルスの活性化がそのメカニズムの一つであることを見出した。本研究から、これまで知られていなかったDOT1L阻害による抗腫瘍効果メカニズムを明らかにした。