Region-specific alteration of histone modification by LSD1 inhibitor conjugated with pyrrole-imidazole polyamide.

Autor: Alagarswamy K; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Shinohara KI; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Takayanagi S; Department of Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan., Fukuyo M; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Okabe A; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Rahmutulla B; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Yoda N; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Qin R; Department of Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan., Shiga N; Department of Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan., Sugiura M; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Sato H; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Kita K; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan., Suzuki T; Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan., Nemoto T; Department of Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan., Kaneda A; Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2018 Jun 29; Vol. 9 (50), pp. 29316-29335. Date of Electronic Publication: 2018 Jun 29 (Print Publication: 2018).
DOI: 10.18632/oncotarget.25451
Abstrakt: Epigenome regulates gene expression to determine cell fate, and accumulation of epigenomic aberrations leads to diseases, including cancer. NCD38 inhibits lysine-specific demethylase-1 (LSD1), a histone demethylase targeting H3K4me1 and H3K4me2, but not H3K4me3. In this study, we conjugated NCD38 with a potent small molecule called pyrrole (Py) imidazole (Im) polyamide, to analyze whether targets of the inhibitor could be regulated in a sequence-specific manner. We synthesized two conjugates using β-Ala (β) as a linker, i.e., NCD38-β-β-Py-Py-Py-Py (NCD38-β 2 P 4 ) recognizing WWWWWW sequence, and NCD38-β-β-Py-Im-Py-Py (NCD38-β 2 PIPP) recognizing WWCGWW sequence. When RKO cells were treated with NCD38, H3K4me2 levels increased in 103 regions with significant activation of nearby genes ( P = 0.03), whereas H3K4me3 levels were not obviously increased. H3K27ac levels were also increased in 458 regions with significant activation of nearby genes ( P = 3 × 10 -10 ), and these activated regions frequently included GC-rich sequences, but less frequently included AT-rich sequences ( P < 1 × 10 -15 ) or WWCGWW sequences ( P = 2 × 10 -13 ). When treated with NCD38-β 2 P 4 , 234 regions showed increased H3K27ac levels with significant activation of nearby genes ( P = 2 × 10 -11 ), including significantly fewer GC-rich sequences ( P < 1 × 10 -15 ) and significantly more AT-rich sequences ( P < 1 × 10 -15 ) compared with NCD38 treatment. When treated with NCD38-β 2 PIPP, 82 regions showed increased H3K27ac levels, including significantly fewer GC-rich sequences ( P = 1 × 10 -11 ) and fewer AT-rich sequences ( P = 0.005), but significantly more WWCGWW sequences ( P = 0.0001) compared with NCD38 treatment. These indicated that target regions of epigenomic inhibitors could be modified in a sequence-specific manner and that conjugation of Py-Im polyamides may be useful for this purpose.
Competing Interests: CONFLICTS OF INTEREST All authors have no conflicts of interest to disclose.
Databáze: MEDLINE
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