Histone H3K79 glutarylation as a novel epigenetic modification linking UV response to prognosis in esophageal squamous cell carcinoma [CUT&Tag]

Methods

Proteomics data of Histone H3 lysine 79 glutarylation (H3K79glu) were obtained from the iProX database (IPX0012762000). A custom H3K79glu antibody was applied to immunohistochemistry in an independent cohort (n = 304), followed by correlation with survival and clinicopathological features. Modifying and demodifying enzymes were determined via inhibitor treatment, overexpression, and siRNA knockdown.

CUT&Tag-seq and RNA-seq were used to map genomic occupancy and functional pathways. Results: H3K79glu was present in both nuclei and cytoplasm of tumor cells, with nuclear levels reduced and cytoplasmic levels elevated in tumors versus adjacent tissues. High cytoplasmic H3K79glu predicted poor survival (P < 0.05) and increased lymph node metastasis, whereas high nuclear H3K79glu predicted favorable outcomes (P < 0.05).

P300 and HDAC8 were identified as the modifying and demodifying enzymes of H3K79glu, respectively. CUT&Tag-seq revealed enrichment of H3K79glu at intronic and distal intergenic regions, particularly within UV-response pathway. Low-dose UV irradiation enhanced H3K79glu deposition, reprogrammed tumor metabolism, and reshaped immune profiles.

Mechanistically, H3K79glu promoted chromatin condensation by increasing nucleosome density, thereby repressing transcription of target genes. Conclusions: H3K79glu is a previously unrecognized histone modification that integrates UV-related transcription-coupled repair with metabolic and immune regulation in ESCC. It represents a promising prognostic biomarker and potential therapeutic target.