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Identifying ST6GAL1 as a novel factor for human dermal fibroblast photoaging

ABSTRACT: Due to increasing global UV exposure from environmental changes and lifestyle factors, understanding the molecular mechanisms of photoaging is critical in dermatological research. This study addresses the underexplored role of glycosylation in dermal fibroblast photoaging by establishing an in vitro model using human dermal fibroblasts (HDF) exposed to UVA. Transcriptomic profiling revealed significant enrichment of gene sets associated with glycosylation and carbohydrate derivative synthesis. We employed lectin arrays and binding assays to identify candidate oligosaccharide ligands responsive to UVA exposure, revealing a marked upregulation of cell-surface sialylation levels during photoaging. Western blot analysis further indicated specific overexpression of the sialyltransferase ST6GAL1 in photoaged HDFs. Intervention with the sialyltransferase inhibitor 3FAx-Neu5Ac or ST6GAL1 gene silencing significantly alleviated the skin photoaging markers including p16, MMPs and SA-β-gal staining, while ST6GAL1 overexpression replicated these photoaging characteristics. Mechanistically, pathway analysis indicated that ST6GAL1 mediates photoaging via the regulation of the RAS-ERK-p16 signaling axis, while treatment with the RAS inhibitor reversed the phenotypic changes induced by ST6GAL1 knockdown. In a reconstructed human skin equivalent model of UVA photoaging, immunostaining confirmed the presence of ST6GAL1 alongside RAS and p16 induction. This study uniquely identifies ST6GAL1 as a specific biomarker for fibroblast photoaging, offering a novel therapeutic target for the diagnosis and intervention of photoaging.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329475 | GEO | 2026/09/02

REPOSITORIES: GEO

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	GSE329475_all_gene_count_matrix.xlsx	Xlsx

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Project description:Sialic acids on vertebrate cell surfaces mediate many biological roles. Altered expression of certain sialic acid types or their linkages can have prognostic significance in human cancer. A classic but unexplained example is enhanced Î±2-6-sialylation on N-glycans, resulting from over-expression of the Golgi enzyme Î²-galactoside:Î±2-6-sialyltransferase (ST6Gal-I). Previous data supporting a role for the resulting SiaÎ±2-3GalÎ²1-4GlcNAc (Sia6LacNAc) structure in tumor biology were based on in vitro studies in transfected carcinoma cells, in which increased Sia6LacNAc on Î²1-integrins enhanced their binding to ligands, and stimulated cell motility. Here we examine for the first time the in vivo role of the ST6Gal-I enzyme in the growth and differentiation of spontaneous mammary cancers in mice transgenic for an MMTV-promoter-driven polyoma-middle-T antigen, a tumor in which beta1-integrin function is important for tumorigenesis, and in maintaining the proliferative state of tumor cells. Tumors induced in St6gal1 null animals were more differentiated in comparison to those in the wild-type background, both by histological analysis and by protein expression profiles. Furthermore, we show the St6gal1 null tumors have selectively altered expression of genes associated with focal adhesion signaling, and have decreased phosphorylation of FAK, a downstream target of Î²1-integrins. This first in vivo evidence for a role of ST6Gal-I in tumor progression was confirmed using a novel approach, which conditionally restored St6gal1 in cell lines derived from the null tumors. These findings indicate a role for ST6Gal-I as a mediator of tumor progression, with its expression causing a less differentiated phenotype, via enhanced Î²1-integrin function. Experiment Overall Design: Messenger RNA from tumors arising in wild-type or St6gal1 null littermates was used for the gene expression analysis on the Mouse Genome 430 2.0 Array (Affymetrix). Six PyV-mT St6gal1 null and wild-type tumor pairs were used, in four independent pools of three tumors each. Each sample is a pool of three different tumors from three different animals. For the first set of microarray analysis samples GSM239969 and GSM239970 were being compared, and in the second set, samples GSM239971 and GSM239972 were compared.

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Identifying ST6GAL1 as a novel factor for human dermal fibroblast photoaging

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