C-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation.

Jie Zhang,Peilang Yang,Xiong Zhang,Dan Liu,Jizhuang Wang,Min Gao,Yan Liu,Xiqiao Wang

doi:10.3389/fendo.2021.676403

Jie Zhang, Peilang Yang + Show 6 more

Open Access

https://doi.org/10.3389/fendo.2021.676403

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Abstract

Keratinocyte differentiation dysfunction in diabetic skin is closely related to impaired skin barrier functions. We investigated the effects of c-Myc and S100A6 on Human immortal keratinocyte line (HaCaT) or keratinocyte differentiation and potential mechanisms. The expression levels of differentiation makers such as transglutaminase 1 (TGM1), loricrin (LOR), and keratin 1 (K1) were significantly reduced, while the expression of c-Myc was significantly increased in HaCaT cells cultured in high glucose and wound margin keratinocytes from diabetic rats and human patients. Overexpression of c-Myc caused differentiation dysfunction of HaCaT, while knocking down c-Myc promoted differentiation. High glucose increased the expression of c-Myc and inhibited differentiation in HaCaT cells by activating the WNT/β-catenin pathway. Moreover, inhibition of c-Myc transcriptional activity alleviated the differentiation dysfunction caused by high glucose or overexpression of c-Myc. c-Myc binds to the S100A6 promoter to directly regulate S100A6 expression and high glucose promoted S100A6 transcription. The expression of S100A6 was increased in HaCaT cultured with high glucose and wound margin keratinocytes from diabetic rats and human patients. However, the expression of S100A6 was decreased during normal HaCaT differentiation. HaCaT cells treated with S100A6 recombinant protein showed differentiation dysfunction. The expressions of TGM1, LOR and K1 in knockdown S100A6 HaCaT cells were higher than those in the control group. Overexpression of c-Myc or high glucose caused differentiation dysfunction of HaCaT cells, and was rescued by knocking down S100A6. These findings illustrate a new mechanism by which c-Myc upregulated by high glucose inhibits HaCaT differentiation by directly activating S100A6 transcription. Thus, c-Myc and S100A6 may be potential targets for the treatment of chronic diabetic wounds.

Highlights

The skin acts as a barrier that helps the body resist external pathogenic microorganisms and maintain a stable internal environment
Our results show that keratinocyte or HaCaT differentiation was impaired in diabetic or high glucose conditions
We explored the mechanism of epidermal differentiation dysfunction in diabetes or high glucose conditions

Summary

Introduction

The skin acts as a barrier that helps the body resist external pathogenic microorganisms and maintain a stable internal environment The epidermis forms this defence barrier during differentiation, which begins when basal keratinocytes exit the cell cycle and move through the basal, spinous, and granular layers, and the stratum corneum [1]. We found that keratinocytes at the diabetic wound margin are characterised by keratinocyte differentiation dysfunction and that c-Myc was upregulated in diabetic wounds (unpublished results).c-Myc regulates the expression of many genes related to cell proliferation, migration, differentiation, and apoptosis [6]. The transgenic mouse overexpressing the c-Myc gene in the epidermis showed high proliferation and inhibited differentiation of keratinocytes [8]. S100A6 promotes the proliferation of endothelial cells and inhibits their differentiation [14]

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