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

Roberta Noberini,Michela Lupia,Giovanni Bertalot,Giuseppina Bonizzi,Marta Tagliabue,Camilla Restellini,Maria Giovanna Jodice,Daniela Osti,Susanna Chiocca,Francesco Raimondi,Evelyn Oliva Savoia,Maria Capra,Fausto Antonio Maffini,Giuliana Pelicci,Lavinia Ghiani,Tiziana Bonaldi,Marco Giordano,Mohssen Ansarin

doi:10.3390/cancers11050723

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.

Highlights

Cancer has been considered as the result of the accumulation of genetic defects, such as mutations and copy number changes
We investigated epigenetic aberrations occurring in tumors, using the following three different strategies: (1) profiling histone H3 post-translational modifications (PTMs) changes in normal and tumor tissues by MS-based methods, (2) verifying whether these changes are due to increased proliferation of tumor cells and whether they are maintained in culture models, and (3) analyzing the differential gene expression levels and the mutations of histone modifying enzymes (HMEs) using publicly available datasets
We found that some changes occurring at the level of histone PTMs and HMEs were specific to a single or a few tumor types, but other changes were much more widespread, suggesting the existence of common epigenetic aberrant mechanisms occurring in cancer

Summary

Introduction

Cancer has been considered as the result of the accumulation of genetic defects, such as mutations and copy number changes. Cancers 2019, 11, 723 epigenetic changes contribute to cancer progression [1]. Epigenetic features include histone post-translational modifications (PTMs), DNA methylation, and nucleosome positioning, which all concur to the regulation of gene expression, determining the fate of the different cell types of an organism starting from the same DNA sequence. The disruption of epigenetic mechanisms can lead to altered gene expression and cellular transformation, which play a crucial role during the initiation and progression of cancer. The type, location, and combination of histone PTMs contribute to the regulation of the underlying DNA by affecting chromatin compaction and accessibility, and by generating binding sites for the recruitment of effector proteins that mediate downstream processes [1,2]

Methods

Results

Conclusion