Inhibiting Hyper-O-GlcNAcylation of c-Myc accelerate diabetic wound healing by alleviating keratinocyte dysfunction
Jie Zhang1, Peilang Yang1, Dan Liu1
1Department of Burn, Ruijin Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Background:
Diabetic foot ulcers characterized by delayed healing are one of the main complications of diabetes. Epidermal keratinocyte dysfunction has been found to play a pivotal role in the poor healing ability of diabetic wounds. In this study, we aimed to explore the relationship between c-Myc and its O-linked N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) modification and keratinocyte dysfunction in diabetic wounds.
Methods:
Clinical wound samples were collected and a full-thickness skin defect wound model of diabetic rats was established. Re-epithelialization of wounds was observed by H&E staining and expressions of proliferating cell nuclear antigen, transglutaminase 1, loricrin, c-Myc and O-GlcNAc were measured by immunohistochemistry. The functional changes of proliferation, migration and differentiation of human immortalized epidermal cells (HaCaT) cells after overexpression or knockdown of c-Myc were observed. O-GlcNAcylation of c-Myc was confirmed using immunoprecipitation and proximity ligation assay. Stability of the c-Myc protein was measured using cycloheximide. Wound healing was observed after topical application of compounds that inhibited c-Myc or O-GlcNAc on diabetic wounds.
Results:
Keratinocytes at the diabetic wound margin were characterized by active proliferation and division, slow migration and poor differentiation. Similar phenomena were observed in HaCaT cells cultured in 30 mM glucose and keratinocytes at the wound margin of the diabetic rats. The expression of c-Myc was increased in keratinocytes at the wound margin of diabetic rats, patients, and in HaCaT cells cultured with 30 mM glucose. Increased expression of c-Myc promoted the proliferation while inhibiting the migration and differentiation of the HaCaT cells, and inhibition of c-Myc promoted diabetic wound healing. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of O-GlcNAc ameliorated keratinocyte dysfunction and promoted diabetic wound healing.
Conclusions:
Increased expression of c-Myc promoted abnormal proliferation and inhibited migration and differentiation of keratinocytes at the diabetic wound margin. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of c-Myc or O-GlcNAc alleviated delayed diabetic wound healing. These findings make c-Myc and O-GlcNAc potential therapeutic targets for diabetic wounds.
Insights
Diabetic wound healing is impaired by keratinocyte dysfunction, driven by increased c-Myc expression and O-linked N-acetylglucosamine (O-GlcNAc) glycosylation. Inhibiting c-Myc or O-GlcNAc can improve healing.
Area of Science:
- Cell Biology
- Dermatology
- Metabolic Disorders
Background:
- Diabetic foot ulcers exhibit delayed healing, a major diabetes complication.
- Epidermal keratinocyte dysfunction is a key factor in poor diabetic wound healing.
- This study investigates the roles of c-Myc and its O-GlcNAcylation in diabetic wound keratinocyte dysfunction.
Purpose of the Study:
- To explore the relationship between c-Myc, O-GlcNAcylation, and keratinocyte dysfunction in diabetic wounds.
- To assess the impact of c-Myc and O-GlcNAc modulation on diabetic wound healing.
- To identify potential therapeutic targets for diabetic wound treatment.
Main Methods:
- Collected clinical wound samples and established a diabetic rat wound model.
- Assessed keratinocyte proliferation, migration, and differentiation markers via immunohistochemistry.
- Utilized cell culture, immunoprecipitation, and cycloheximide assays to study c-Myc and O-GlcNAcylation.
- Investigated the therapeutic potential of inhibiting c-Myc or O-GlcNAc in diabetic wounds.
Main Results:
- Diabetic wound keratinocytes showed increased proliferation, reduced migration, and poor differentiation.
- Elevated c-Myc expression and O-GlcNAcylation were observed in diabetic wound keratinocytes.
- Overexpression of c-Myc exacerbated keratinocyte dysfunction, while its inhibition improved wound healing.
- Inhibition of O-GlcNAc ameliorated keratinocyte dysfunction and promoted diabetic wound healing.
Conclusions:
- Increased c-Myc and its O-GlcNAcylation contribute to keratinocyte dysfunction and delayed healing in diabetic wounds.
- Targeting c-Myc or O-GlcNAc pathways presents a promising therapeutic strategy for diabetic wound management.
- These findings highlight c-Myc and O-GlcNAc as potential therapeutic targets for improving diabetic wound healing.
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