TY - JOUR
T1 - Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9
AU - Li, Guodong
AU - Li, Dan
AU - Wu, Chun
AU - Li, Shengnan
AU - Chen, Feng
AU - Li, Peng
AU - Ko, Chung Nga
AU - Wang, Wanhe
AU - Lee, Simon Ming Yuen
AU - Lin, Ligen
AU - Ma, Dik Lung
AU - Leung, Chung Hang
N1 - Funding Information:
This work is supported by the National Natural Science Foundation of China, China (22077109, 21775131 and 82073715), the HKBU SKLEBA Research Grant (SKLP_2223_P03), the Science and Technology Development Fund, Macau SAR (File no. 0007/2020/A1), SKL-QRCM(UM)-2020-2022, and the University of Macau (MYRG2019-00002-ICMS, MYRG2020-00091-ICMS and MYRG2020-00017-ICMS).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85134480258&partnerID=8YFLogxK
U2 - 10.1038/s12276-022-00804-1
DO - 10.1038/s12276-022-00804-1
M3 - Journal article
C2 - 35859119
AN - SCOPUS:85134480258
SN - 1226-3613
VL - 54
SP - 988
EP - 998
JO - Experimental and Molecular Medicine
JF - Experimental and Molecular Medicine
IS - 7
ER -
