Abstract
BackgroundEpigenetic alterations have been recognized as important contributors to the pathogenesis of PDAC. However, the role of histone variants in pancreatic tumor progression is still not completely understood. The aim of this study was to explore the expression and prognostic significance of histone protein variants in PDAC patients.MethodsLiquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed for qualitative analysis of histone variants and histone related post-translational modifications (PTMs) in PDAC and normal pancreatic tissues. Survival analysis was conducted using the Kaplan-Meier method and Cox proportional hazards regression.ResultsHistone variant H1.3 was found to be differentially expressed (p = 0.005) and was selected as a PDAC specific histone variant candidate. The prognostic role of H1.3 was evaluated in an external cohort of patients with resected PDAC using immunohistochemistry. Intratumor expression of H1.3 was found to be an important risk factor for overall survival in PDAC, with an adjusted HR value of 2.6 (95% CI 1.1–6.1), p = 0.029.ConclusionWe suggest that the intratumor histone H1.3 expression as reported herein, may serve as a new epigenetic biomarker for PDAC.
Highlights
Epigenetic alterations have been recognized as important contributors to the pathogenesis of Pancreatic ductal adenocarcinoma (PDAC)
Analysis of the histone profile in PDAC using LC-MS/MS Profile of histone variants and histone related post-translational modifications (PTMs) Overall, it was possible to classify between 1281 and 2767 protein identifications of which 11 to 16 different histone variants were detected in individual samples
Even though the sequence coverage was substantially improved by using additional digestion enzyme, the sequence coverages for the reported histone variants varied between 12.45% and 73.02%
Summary
Epigenetic alterations have been recognized as important contributors to the pathogenesis of PDAC. The role of histone variants in pancreatic tumor progression is still not completely understood. The aim of this study was to explore the expression and prognostic significance of histone protein variants in PDAC patients. It is apparent that, besides the extensive genetic alterations, an aberrant epigenetic regulation, including modifications of the chromatin structure, significantly contributes to the pathogenesis of PDAC [5,6,7]. Chromatin depositions of histone variants have been implicated in the establishment and maintenance of the epigenetic states. Variants of histone proteins are further involved in fundamental cellular processes, such as regulation of transcriptional activity or DNA repair, considered as contributors to tumor progression [8, 9]
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