Lee Min Gyu, Wynder Christopher, Schmidt Dawn M, McCafferty Dewey G, Shiekhattar Ramin
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Chem Biol. 2006 Jun;13(6):563-7. doi: 10.1016/j.chembiol.2006.05.004.
Demethylation of histone H3 lysine 4 is carried out by BHC110/LSD1, an enzyme with close homology to monoamine oxidases (MAO). Monoamine oxidase A or B are frequent targets of selective and nonselective small molecular inhibitors used for treatment of depression. Here we show that in contrast to selective monoamine oxidase inhibitors such as pargyline, nonselective monoamine oxidase inhibitors potently inhibit nucleosomal demethylation of histone H3 lysine 4. Tranylcypromine (brand name Parnate) displayed the best inhibitory activity with an IC50 of less than 2 microM. Treatment of P19 embryonal carcinoma cells with tranylcypromine resulted in global increase in H3K4 methylation as well as transcriptional derepression of two BHC110 target genes, Egr1 and the pluripotent stem cell marker Oct4. These results attest to the effectiveness of tranylcypromine as a small molecular inhibitor of histone demethylation.
组蛋白H3赖氨酸4的去甲基化由BHC110/LSD1完成，这是一种与单胺氧化酶（MAO）具有高度同源性的酶。单胺氧化酶A或B是用于治疗抑郁症的选择性和非选择性小分子抑制剂的常见靶点。在此我们表明，与如帕吉林这样的选择性单胺氧化酶抑制剂不同，非选择性单胺氧化酶抑制剂能有效抑制组蛋白H3赖氨酸4的核小体去甲基化。反苯环丙胺（商品名Parnate）表现出最佳抑制活性，IC50小于2微摩尔。用反苯环丙胺处理P19胚胎癌细胞导致H3K4甲基化整体增加以及两个BHC110靶基因Egr1和多能干细胞标志物Oct4的转录去抑制。这些结果证明反苯环丙胺作为组蛋白去甲基化小分子抑制剂的有效性。
