Global profile of histone marks at distinct stages of melanoma progression and its impact on malignancy characteristics

Abstract

Cutaneous melanoma resulting from the malignant transformation of melanocytes is the most aggressive type of skin tumors, the incidence of which is progressively increasing in the world. Recent studies demonstrate changes in epigenetic marks that are involved in the development and progression of this tumor, among these epigenetic modifications are posttranslational modifications (PTMs) in histones. In nucleosomes, DNA is associated with histones and the PTMs these proteins carry interfere not only with this association, but also with the control of repressor complexes or transcription activators, and with proteins in DNA repair and replication. Although much less studied than changes in DNA methylation, changes in histone PTMs are present in tumor cells. However, knowledge about the role of different PTMs in histones in tumor development and progression is still scarce. Therefore, our project aims to perform quantitative proteomic analysis to investigate the profiles of histone markers in a more global way in cell lines that correspond to distinct stages of the genesis and evolution of melanoma. Subsequently, based on RNA sequencing data from the same cell lines, already obtained in our laboratory, we will identify histone modifying enzymes with altered expression and that may be involved with the change of the marks in the histones identified in the proteomic analysis. We will validate the expression profile of these enzymes and characterize the impact of their inhibition on tumor characteristics such as proliferation, migration, invasion and tumorigenesis in vivo. This study may contribute not only to the knowledge about the role of PTMs in histones in the genesis and evolution of melanoma, but also result in a potential identification of prognostic markers of the disease.