Integrated ATAC-Seq and RNA-Seq Identify ATF3 as a Tumor Suppressor in UVB-Induced Keratinocyte Carcinogenesis

Current approaches for preventing and suppressing the initiation and development of keratinocyte carcinoma remain limited, highlighting the urgent need to identify novel targets for tumor intervention. As major environmental pathogenic factor, chronic ultraviolet B (UVB) exposure promotes keratinocyte malignant transformation through epigenetic reprogramming, reshaping chromatin accessibility and gene expression program, which has not been fully elucidated. Here, we established a chronic UVB irradiation model to induce malignant transformation of keratinocytes and performed integrative analyses using ATAC-seq and RNA-seq. We identified 4903 differentially accessible regions (DARs), with increased accessibility at loci of tumor-promoting genes such as TP63, KRT13, KLF8, and EGFR, and enrichment of AP-1 family motifs. RNA-seq revealed 1136 differentially expressed genes (DEGs), predominantly enriched in inflammatory pathways. Integrative analysis highlighted concordant enrichment of inflammation-related genes within open chromatin regions. ATF3 was selected and its downregulated identified after UVB exposure. Functional assays confirmed that ATF3 represses chronic UVB-induced malignant transformation of keratinocytes. Notably, ChIP-qPCR validation verified GDA (Guanine deaminase) as the direct downstream target gene of ATF3. Reduced ATF3 binding elevates GDA promoter chromatin accessibility and upregulates GDA expression to drive malignant progression. In conclusion, our findings demonstrate that chronic UVB exposure remodels chromatin and transcriptomic landscapes and identify ATF3 and its direct target GDA as a critical tumor-suppressive regulatory module for UVB-induced keratinocyte carcinoma.