Profiling of Epigenetic Features in Clinical Samples Reveals Novel Widespread Changes in Cancer

Abstract

Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in cancer could have important implications for the discovery of both biomarkers for patient stratification and novel epigenetic targets. In this study, we employed mass spectrometry-based approaches to comprehensively profile histone H3 PTMs in a panel of normal and tumoral tissues for different cancer types, identifying various changes, some of which appear to be a consequence of the increased proliferation rate of tumors, while others are cell-cycle independent. Histone PTM changes found in tumors partially correlate with alterations of the gene expression profiles of HMEs obtained from publicly available data and are generally lost in culture conditions. Through this analysis, we identified tumor- and subtype-specific histone PTM changes, but also widespread changes in the levels of histone H3 K9me3 and K14ac marks. In particular, H3K14ac showed a cell-cycle independent decrease in all the seven tumor/tumor subtype models tested and could represent a novel epigenetic hallmark of cancer.

Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes

“…The prediction from these observations (and the fact that almost all histone tails carry some level of K27/K36 methylation) is that the K27/K36 methylation antagonism stabilizes epigenetic states and provides a barrier to changes in cell identity that can be overridden globally by cell proliferation. Recently, profiling histone modifications in tumor samples has revealed pervasive K27me3 loss and K36me2 gain across different cancers (Noberini et al, 2019). We provide evidence that an increased rate of cell division alone might lead to the loss of K27me3 by dilution (this paper; Alabert et al, 2015).…”

A novel proteomics approach to epigenetic profiling of circulating nucleosomes

“…Currently, most of blood proteomic work has been conducted to analyze total protein abundance, with very few studies to analyze specifically circulating nucleosomes/histones 18 . Mass spectrometry studies on histones PTMs have been mostly conducted on cell lines or tissues 19 – 21 . Indeed, one challenge to study histones PTMs in blood is the matrix complexity where the high protein content and the abundance of blood proteins may mask histones PTMs.…”

Spatial epi-proteomics enabled by histone post-translational modification analysis from low-abundance clinical samples

“…In particular, altered levels of histone post-translational modifications (PTMs) have been found in a multitude of diseased states. In cancer, specific histone PTM changes have been proposed as general hallmarks of cancer [1,2], as prognostic biomarkers [3][4][5][6] and as useful tools for cancer detection and diagnosis [7,8]. The widespread presence of histone PTM aberrations in tumors is in accordance with the observation that the enzymes responsible for the addition and removal of histone PTMs are among the most frequently mutated class of genes in cancer [9].…”