Altered Histone Modifications in Cancer

Chapter

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.

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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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Pharmacology and TherapeuticsRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Institute of Biomedical Research, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK

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