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Study of the Effects of Inhibition of Epigenetic Regulators on the Proliferation of Hematological Malignant Tumor Cells

中山, 和英 筑波大学 DOI:10.15068/0002000840

2021.08.02

概要

Epigenetics is the study of changes in gene function and expression that are heritable and that are not accompanied by alterations of the DNA sequence. The epigenetic modification consists of specific covalent modifications of chromatin components, which include DNA methylation and post- translational histone modifications. DNA methylation in promoter region represses gene expression by recruiting transcriptional repressor proteins or by inhibiting the binding of transcription factors to DNA. Histone modifications including methylation, acetylation, phosphorylation and ubiquitylation can modulate chromatin structure and hence influence gene expression, though the effect of these modifications on gene expression is largely context dependent. It is well known that genetic aberrations, such as point mutations, chromosomal mutations or changes in the gene copy number play an important role in cancer cell initiation and progression. In addition, recent growing evidences have indicated that the vast majority of human cancers harbor not only genetic, but also epigenetic abnormalities. Targeting these epigenetic aberrations in an attempt to restore a more normal condition seems an important treatment strategy for cancer. In fact, there are the large amount of effort that has been directed towards the development of epigenetics-targeting anti-cancer drugs. A few drugs targeting epigenetic enzymes have been approved by U.S. Food and Drug Administration (FDA), and a wide range of epigenetics-targeted drugs are undergoing clinical trials.

To investigate novel therapeutic strategies that modulate epigenetic dysregulation in cancer cells, I have researched lysine specific demethylase 1 (LSD1) and protein arginine methyltransferase 4 (PRMT4) as anti-cancer drug targets. In part 1, I investigated a synergistic interaction between LSD1 inhibitor, T-3775440, and NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, in acute myeloid leukemia (AML) cells, highlighting the molecular mechanisms underlying the synergy and robust in vitro and in vivo antileukemic effects. In part 2, I found TP-064, which was a potent, selective, and cell-active chemical probe of human PRMT4 and its anti-proliferative activity in multiple myeloma (MM) cells. These results suggest that simultaneous suppression of LSD1 and NAE activities and suppression of PRMT4 activity can serve as novel therapeutic strategies for the treatment of AML and MM, respectively.

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