Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 18-32 |
| Number of pages | 15 |
| Journal | Biochemical Pharmacology |
| Volume | 121 |
| DOIs | |
| Publication status | Published - 1 Dec 2016 |
Keywords
- Angiogenesis process
- Arginine/lysine histone methyltransferases
- Endothelial cells
Cite this
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Pharmacological inhibition of arginine and lysine methyltransferases induces nuclear abnormalities and suppresses angiogenesis in human endothelial cells. / Balcerczyk, Aneta; Rybaczek, Dorota; Wojtala, Martyna; Pirola, Luciano; Okabe, Jun; El-Osta, Assam.
In: Biochemical Pharmacology, Vol. 121, 01.12.2016, p. 18-32.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Pharmacological inhibition of arginine and lysine methyltransferases induces nuclear abnormalities and suppresses angiogenesis in human endothelial cells
AU - Balcerczyk, Aneta
AU - Rybaczek, Dorota
AU - Wojtala, Martyna
AU - Pirola, Luciano
AU - Okabe, Jun
AU - El-Osta, Assam
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - Angiogenesis process
KW - Arginine/lysine histone methyltransferases
KW - Endothelial cells
UR - http://www.scopus.com/inward/record.url?scp=84997113377&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2016.09.013
DO - 10.1016/j.bcp.2016.09.013
M3 - Article
VL - 121
SP - 18
EP - 32
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
ER -