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Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9
Li, Guodong1,2; Li, Dan1; Wu, Chun3; Li, Shengnan1; Chen, Feng1; Li, Peng1; Ko, Chung Nga3; Wang, Wanhe3,4; Lee, Simon Ming Yuen1; Lin, Ligen1; Ma, Dik Lung3; Leung, Chung Hang1,2,5
2022-07-20
Source PublicationExperimental and Molecular Medicine
ISSN1226-3613
Abstract

In hypoxia and hyperglycemia, SET7/9 plays an important role in controlling HIF-1α methylation and regulating the transcription of HIF-1α target genes, which are responsible for angiogenesis and wound healing. Here, we report the Ir(III) complex Set7_1a bearing acetonitrile (ACN) ligands as a SET7/9 methyltransferase inhibitor and HIF-1α stabilizer. Interestingly, Set7_1a could engage SET7/9 and strongly inhibit SET7/9 activity, especially after preincubation with homocysteine (Hcy), which is elevated in diabetes. We hypothesize that Set7_1a exchanges ACN subunits for Hcy to disrupt the interaction between SET7/9 and SAM/SAH, which are structurally related to Hcy. Inhibition of SET7/9 methyltransferase activity by Set7_1a led to reduced HIF-1α methylation at the lysine 32 residue, causing increased HIF-1α level and recruitment of HIF-1α target genes that promote angiogenesis, such as VEGF, GLUT1, and EPO, in hypoxia and hyperglycemia. Significantly, Set7_1a improved wound healing in a type 2 diabetic mouse model by activating HIF-1α signaling and downstream proangiogenic factors. To our knowledge, this is the first Hcy-targeting iridium compound shown to be a SET7/9 antagonist that can accelerate diabetic wound healing. More importantly, this study opens a therapeutic avenue for the treatment of diabetic wounds by the inhibition of SET7/9 lysine methyltransferase activity.

DOI10.1038/s12276-022-00804-1
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaBiochemistry & Molecular Biology ; Research & Experimental Medicine
WOS SubjectBiochemistry & Molecular Biology ; Medicine, Research & Experimental
WOS IDWOS:000829652400001
Scopus ID2-s2.0-85134480258
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Cited Times [WOS]:1   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionDEPARTMENT OF PHARMACEUTICAL SCIENCES
Institute of Chinese Medical Sciences
THE STATE KEY LABORATORY OF QUALITY RESEARCH IN CHINESE MEDICINE (UNIVERSITY OF MACAU)
DEPARTMENT OF BIOMEDICAL SCIENCES
Corresponding AuthorLin, Ligen; Ma, Dik Lung; Leung, Chung Hang
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
2.Zhuhai UM Science and Technology Research Institute, Zhuhai, 519031, China
3.Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong
4.Institute of Medical Research, Northwestern Polytechnical University, Xi’an, Shaanxi, China
5.Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences;  Faculty of Health Sciences
Recommended Citation
GB/T 7714
Li, Guodong,Li, Dan,Wu, Chun,et al. Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9[J]. Experimental and Molecular Medicine,2022.
APA Li, Guodong,Li, Dan,Wu, Chun,Li, Shengnan,Chen, Feng,Li, Peng,Ko, Chung Nga,Wang, Wanhe,Lee, Simon Ming Yuen,Lin, Ligen,Ma, Dik Lung,&Leung, Chung Hang.(2022).Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9.Experimental and Molecular Medicine.
MLA Li, Guodong,et al."Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9".Experimental and Molecular Medicine (2022).
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