Epiproteomic profiling identifies histone H4 hyperacetylation as a prognostic marker in pleural mesothelioma

Pleural mesothelioma (PM) is an aggressive tumor that arises from mesothelial cells as a consequence of asbestos exposure. Despite recent therapeutic advances, the prognosis of PM remains poor, with a median overall survival typically below 18 months. Here, we investigated the association between alterations in histone post-translational modifications (PTMs) and patient survival in PM by employing state-of-the-art mass spectrometry-based epiproteomics. We profiled a cohort of 96 primary tumors obtained at diagnosis, including a subset of 25 patients with matched pre- and post-neoadjuvant treatment samples. Patients were stratified by overall survival using a 15-month cutoff, which approximates the reported median survival for PM. Several PTMs in treatment-naïve tumors, as well as a few therapy-induced changes, showed significant differences between short- and long-survivors across the different patient groups. Hyper-acetylation of the histone H4 tail at basal level was significantly and consistently increased in patients with worse prognosis, both in the entire cohort and within individual groups, and was associated with worse overall survival in Kaplan-Meier analyses. This association was independent of established clinicopathological variables in multivariable Cox regression models. Interestingly, increased histone H4 hyperacetylation was observed across multiple tumor types, supporting its broader relevance in cancer biology. In vitro, inhibition of histone acetyltransferases reduced PM cell viability and enhanced sensitivity to cisplatin in a synergistic manner. These findings identify histone H4 hyperacetylation as an independent prognostic biomarker in PM and highlight epigenetic modulation as a potential therapeutic avenue in PM.