Pharmacological inhibition of arginine and lysine methyltransferases induces nuclear abnormalities and suppresses angiogenesis in human endothelial cells

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• 作者：Aneta Balcerczyk^a ; ^{abal@biol.uni.lodz.pl" class="auth_mail" title="E-mail the corresponding author} ; Dorota Rybaczek^b ; Martyna Wojtala^a ; Luciano Pirola^c ; Jun Okabe^d ; ^f ; Assam El-Osta^d ; ^e ; ^f
• 关键词：AdoMet ; S-adenosyl-l-methionine ; AMI-1 ; arginine N-methyltransferase inhibitor-1 ; AMI-5 ; arginine(lysine) N-methyltransferase inhibitor-5 ; DAPI ; 4&prime ; 6-diamidino-2-phenylindole ; DNMTs ; DNA methyltransferases ; FDA ; Food and Drug Administration ; HDACs ; histone deacetylases ; HMEC-1 ; immortalized human microvascular endothelial cells ; HKTMs ; histone lysine methyltransferases ; HUVECs ; human umbilical vein endothelial cells ; EdU ; 5-ethyl-2&prime ; -deoxyuridine ; MIF ; mean intensity fluorescence ; PI
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：121
• 期：Complete
• 页码：18-32
• 全文大小：2606 K

文摘

Posttranslational modifications of histone tails can alter chromatin structure and regulate gene transcription. While recent studies implicate the lysine/arginine protein methyltransferases in the regulation of genes for endothelial metabolism, the role of AMI-1 and AMI-5 compounds in angiogenesis remains unknown. Here, we show that global inhibition of arginine and lysine histone methyltransferases (HMTs) by AMI-5 induced an angiostatic profile in human microvascular endothelial cells and human umbilical vein endothelial cells. Based on FACS analysis, we found that inhibition of HMTs significantly affects proliferation of endothelial cells, by suppressing cell cycle progression in the G₀/G₁ phase. Immunofluorescent studies of the endothelial cells replication pattern by 5-ethynyl-2′-deoxyuridine incorporation disclosed that AMI-5, and the arginine methyltransferase inhibitor AMI-1, induced heterochromatin formation and a number of nuclear abnormalities, such as formation of micronuclei (MNs) and nucleoplasmic bridges (NPBs), which are markers of chromosomal instability. In addition to the modification of the cell cycle machinery in response to AMIs treatment, also endothelial cells migration and capillary-like tube formation processes were significantly inhibited, implicating a stimulatory role of HMTs in angiogenesis.