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Misregulation of DNA Methylation Regulators in Cancer

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DNA and Histone Methylation as Cancer Targets

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Epigenetic modifications at the DNA level play a central role in establishing the chromatin state and thereby influencing biological function. Several disorders arise from aberrant epigenetic patterns on DNA, cancer being widely explored as an epigenetic disorder. In fact several cancers are associated with a hypermethylator phenotype, which essentially functions as a ‘driver’ of tumorigenesis. Aberrant DNA methylation patterns arise from disrupting the ‘writers’ or ‘erasers’ of the DNA methylation pathway, coordinately functioning to regulate DNA epigenetic marks. Cancer associated deregulatory mechanisms targeting functional disruption of the molecular components of the DNA methylation pathway, and their contribution to cancer initiation and progression are being increasingly appreciated. Understanding these mechanisms of deregulation is central to identifying new targets for therapeutic intervention, in both cancer prevention and treatment.

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Abbreviations

AML:

Acute Myeloid Leukemia

CGI:

CpG island

CIMP:

CpG hypermethylator phenotype

DNMT:

DNA methyltransferase

EBF1:

Early B-Cell Factor 1

EMT:

Epithelial to mesenchymal transition

FH:

Fumarate hydratase (fumarase)

G-CIMP:

Glioma specific CIMP

GSC:

Glioblastoma Stem Cells

HIF:

Hypoxia inducible factor

HPC:

Hematopoietic presursor cells

HRE:

Hypoxia response element

HSC:

Hematopoietic stem cells

IDAX:

Inhibition of the Dvl and Axin Complex

IDH:

Isocitrate dehydrogenase

MBD:

Methyl binding domain

mCG:

CpG methylation

mCH:

Non-CpG methylation

MDS:

Myelodysplastic Syndromes

MLL:

Mixed-lineage leukemia

MPN:

Myeloproliferative Neoplasm

MTase:

Methyltransferase

PCNA:

Proliferating cell nuclear antigen

SDH:

Succinate dehydrogenase

TDG:

Thymine-DNA glycosylase

TET:

Ten-eleven translocation

UHRF:

Ubiquitin-Like with PHD and Ring Finger Domains

α-KG:

Alpha-ketoglutarate

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA

    Joyce J. Thompson & Keith D. Robertson

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  1. Joyce J. Thompson
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  2. Keith D. Robertson
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Correspondence to Keith D. Robertson .

Editor information

Editors and Affiliations

  1. Graduate School of Medicine, Chiba University, Chiba, Chiba, Japan

    Atsushi Kaneda

  2. Advanced Biological Information Research Division, INAMORI Frontier Research Center, Kyushu University, Fukuoka, Fukuoka, Japan

    Yu-ichi Tsukada

Glossary

CpG site

Linear sequence of DNA where a cytosine is followed by guanine in the 5' to 3' direction.

CpG methylation (mCG)

Cytosine within a CpG site, methylated by the DNMTs at the C5 position, represented as mCG.

Non CpG methylation (mCH)

Methylation occurring outside of CpG sites, where H could be adenine, cytosine or thymine.

CpG Islands (CGI)

Short interspersed sequence of DNA, around 200 base-pairs long, with high CpG fequency, and GC content greater than 50%.

CpG shores and shelves

2 kb on either side of CpG islands are termed CpG shores, and 2 kb on either side of the CGI shores are termed CGI shelves.

CpG Canyons

Regions of low methylation, distinct from CGIs, and frequently associated with transcription factor binding sites.

Epimutations

Non-genetic, heritable, aberrant lesions in the expression of a gene, arising from epigenetic DNA modifications or other epigenetic modifications on local chromatin.

CpG hypermethylator phenotype (CIMP)

Hypermethylated CpG islands forming a diagnostic/prognostic tumor specific DNA methylation signature.

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Thompson, J.J., Robertson, K.D. (2017). Misregulation of DNA Methylation Regulators in Cancer. In: Kaneda, A., Tsukada, Yi. (eds) DNA and Histone Methylation as Cancer Targets. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-59786-7_5

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  • DOI: https://doi.org/10.1007/978-3-319-59786-7_5

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