Role of novel histone modifications in cancer

Abstract

Oncogenesis is a multistep process mediated by a variety of factors including epigenetic modifications. Global epigenetic post-translational modifications have been detected in almost all cancers types. Epigenetic changes appear briefly and do not involve permanent changes to the primary DNA sequence. These epigenetic modifications occur in key oncogenes, tumor suppressor genes, and transcription factors, leading to cancer initiation and progression. The most commonly observed epigenetic changes include DNA methylation, histone lysine methylation and demethylation, histone lysine acetylation and deacetylation. However, there are several other novel post-translational modifications that have been observed in recent times such as neddylation, sumoylation, glycosylation, phosphorylation, poly-ADP ribosylation, ubiquitination as well as transcriptional regulation and these have been briefly discussed in this article. We have also highlighted the diverse epigenetic changes that occur during the process of tumorigenesis and described the role of histone modifications that can occur on tumor suppressor genes as well as oncogenes, which regulate tumorigenesis and can thus form the basis of novel strategies for cancer therapy.

Keywords: cancer; histones; oncogenes; tumor suppressor genes; ubiquitination.

Figure 1. Writers, readers and erasers of histone marks

Reversible PTMs addition, identification and removal of these modifications on histone tails regulate various biological processes, including transcription, DNA replication and DNA repair and are highly dynamic in nature. The "writers" such as histone protein kinases add specific PTMs on specific amino acid residues on core histone tails. These marks are identified by specific protein domains called "readers" such as 14-3-3 proteins. The PTM marks are removed by active enzymes known as "erasers" such as phosphatases; Abbreviations: RSK, ribosomal protein S6 kinase A3; AuroraB, serine/threonine protein kinase Aurora B; PKM2, pyruvate kinase M2; Msk1/2, Mitogen- and stress-activated protein kinase 1 and 2, PP, protein phosphatases.