A molecular landscape and prognosis signature based on histone tyrosine sulfation in pan-cancer analysis

Abstract

Background: Tyrosine sulfation, a widespread post-translational modification in mammals mainly associated with secretory and transmembrane proteins, has recently been found to occur on histones. However, the molecular landscape and prognostic signature of pan-cancer based on histone tyrosine sulfation (HYsulf) remain poorly understood.

Methods: We investigated the expression diversity, molecular regulation landscape, DNA methylation and mutation patterns of 51 HYsulf-related genes across 33 cancer types from the Cancer Genome Atlas (TCGA). Additionally, we classified pan-cancer samples into high- and low-score subgroups (Hscore and Lscore) by establishing the HYsulf score.

Result: Enrichment analysis revealed high enrichment of immune-related pathways, cancer-associated hallmarks and pathways, hypoxia, metabolism and cell fate-related pathways in the Hscore subgroup. Infiltration analysis indicated correlations between immune infiltration and HYsulf score, with negative associations observed primarily with activated and resting NK cells, while positive correlations were prominent with Tregs, macrophages M1 and M0. HYsulf score showed significant correlations with immuno-inhibitors, immuno-stimulators, MHC, chemokines and their receptors, as well as emerging biomarkers of immune therapeutic response such as TMB, MSI and neoantigens. Furthermore, evaluations of seven metabolic features suggested a strong link between HYsulf and metabolic reprogramming in pan-cancer. Additionally, drug response evaluation using the CellMiner database uncovered candidate compounds associated with HYsulf-related genes. Importantly, the HYsulf score demonstrated prognostic stratification capacity in predicting overall survival or progression-free time in 10 tumour types. Finally, the nomogram based on the HYsulf score was established for prognostic prediction of PCPG and UVM.

Conclusion: We developed a HYsulf-associated transcriptomic signature based on HYsulf that holds promise for predicting prognosis and drug response.

Keywords

histone tyrosine sulfation / molecular landscape / pan-cancer / prognosis signature

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2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.