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Altered Histone Modifications in Cancer

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Epigenetic Alterations in Oncogenesis

Part of the book series: Advances in Experimental Medicine and Biology ((volume 754))

Abstract

In human health and disease the choreographed actions of a wide armory of transcription factors govern the regulated expression of coding and nonprotein coding genes. These actions are central to human health and are evidently aberrant in cancer. Central components of regulated gene expression are a variety of epigenetic mechanisms that include histone modifications. The post-translational modifications of histones are widespread and diverse, and appear to be spatial-­temporally regulated in a highly intricate manner. The true functional consequences of these patterns of regulation are still emerging. Correlative evidence supports the idea that these patterns are distorted in malignancy on both a genome-wide and a discrete gene loci level. These patterns of distortion also often reflect the altered expression of the enzymes that control these histone states. Similarly gene expression patterns also appear to reflect a correlation with altered histone modifications at both the candidate loci and genome-wide level. Clarity is emerging in resolving these relationships between histone modification status and gene expression ­patterns. For example, altered transcription factor interactions with the key co-activator and co-repressors, which in turn marshal many of the histone-modifying enzymes, may distort regulation of histone modifications at specific gene loci. In turn these aberrant transcriptional processes can trigger other altered epigenetic events such as DNA methylation and underline the aberrant and specific gene expression patterns in cancer. Considered in this manner, altered expression and recruitment of histone-modifying enzymes may underline the distortion to transcriptional responsiveness observed in malignancy. Insight from understanding these processes addresses the challenge of targeted epigenetic therapies in cancer.

Chromatin-modifying enzymes: The nomenclature for enzymes involved in protein methylation, demethylation, and acetylation has recently been rationalized (Allis CD et al (2007) New nomenclature for chromatin-modifying enzymes. Cell 131:633–636). In this review, we use the new nomenclature for lysine methyltransferases (KMT), lysine demethylases (KDM), and lysine acetyltransferases (KAT). Histone deacetylases (HDACs) have retained their original nomenclature. To maintain a link between the new nomenclature and the literature, we use both the new designation and the original published designation(s), e.g., KDM5A/JARID1A/RBP2.

Histone modifications: We use the Brno nomenclature for histone modifications (Turner BM (2005) Reading signals on the nucleosome with a new nomenclature for modified histones. Nat Struct Mol Biol 12:110–112). For example, histone H3 tri-methylated at lysine 4 is shown as H3K4me3.

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Abbreviations

AR:

Androgen receptor

ChIP:

Chromatin immunoprecipitation

CoA:

Co-activator complex

E2 :

Estradiol

ERα:

Estrogen receptor alpha

ES:

Embryonic stem cell

HDAC:

Histone deacetylase

JMJD:

Jumonji domain containing protein

JARID:

Jumonji AT-rich interactive domain

KAT:

Lysine acetyltransferase

KDM:

Lysine demethylase

KMT:

Lysine methyltransferase

LSD1:

Lysine-specific demethylase 1

NCOR:

Nuclear co-repressor

NR:

Nuclear receptor

PSA:

Prostate-specific antigen

SET:

Su(var), enhancer of zeste and trithorax

TF:

Transcription factor

TSA:

Trichostatin A

TSS:

Transcription start site

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Moray J. Campbell

  2. Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK

    Bryan M. Turner

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Correspondence to Moray J. Campbell .

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  1. University of Nebraska Medical Center, Eppley Institute for Research in Cancer, 985950 Nebraska Medical Center, Omaha, 68198, Nebraska, USA

    Adam R. Karpf

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Campbell, M.J., Turner, B.M. (2013). Altered Histone Modifications in Cancer. In: Karpf, A. (eds) Epigenetic Alterations in Oncogenesis. Advances in Experimental Medicine and Biology, vol 754. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9967-2_4

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