Review
Chromatin-remodelling mechanisms in cancer

This paper has been dedicated to the memory of our friend and colleague María Mühlmann.
https://doi.org/10.1016/j.mrrev.2008.01.008Get rights and content

Abstract

Chromatin-remodelling mechanisms include DNA methylation, histone-tail acetylation, poly-ADP-ribosylation, and ATP-dependent chromatin-remodelling processes. Some epigenetic modifications among others have been observed in cancer cells, namely (1) local DNA hypermethylation and global hypomethylation, (2) alteration in histone acetylation/deacetylation balance, (3) increased or decreased poly-ADP-ribosylation, and (4) failures in ATP-dependent chromatin-remodelling mechanisms. Moreover, these alterations can influence the response to classical anti-tumour treatments. Drugs targeting epigenetic alterations are under development. Currently, DNA methylation and histone deacetylase inhibitors are in use in cancer therapy, and poly-ADP-ribosylation inhibitors are undergoing clinical trials. Epigenetic therapy is gaining in importance in pharmacology as a new tool to improve anti-cancer therapies.

Section snippets

Epigenetics and cancer

Epigenetics refers to modifications in genome function that occur without changes in DNA. Eu- or heterochromatic organizations, once established can be somatically maintained as heritable epigenetic states [1], [2]. Chromatin conformation depends on several epigenetic processes acting in concert, such as DNA methylation, histone-tail acetylation, poly-ADP-ribosylation and ATP-dependent chromatin-remodelling mechanisms (i.e. SWI/SNF, ISWI). Distinct histone covalent modifications on a specific

DNA methylation

DNA methylation is a chemical heritable modification characterized by the covalent addition of a methyl group to cytosines. In human somatic cells, DNA methylation typically occurs at CpG dinucleotides, which accounts for ∼1% of the total genome [15]. Moreover, 60–90% of all disperse CpG sequences are methylated. On the other hand, CpG islands (GC-rich regions located at the 5′ ends in ∼60% of human genes) possess high relative densities of unmethylated CpG dinucleotides at all stages of

Histone acetylation

Histone acetylation is the most frequent post-translational histone modification, consisting on the addition of acetyl groups to lysines mostly from the amino-terminal tails of core histones (Fig. 3) [87]. More recently, it has been demonstrated acetylation at the histone core domains, which can be involved in the recruitment of ATP-dependent chromatin-remodelling complexes [88], [89]. The acetylation pattern depends on the activity of histone acetyltransferases (HATs) and histone deacetylases

Poly-ADP-ribosylation

NAD+ can be hydrolyzed by various enzymatic activities, such as PARPs, MARTs, SIRTs and ADP-ribosyl cyclases, which release nicotinamide (Nam) from NAD+ to produce poly-ADP-ribose, mono-ADP-ribosyl-protein, acetyl-ADP-ribose or cyclic-ADP-ribose, respectively (Fig. 4). An ADP-ribosylation reaction involves the cleavage of NAD+ in nicotinamide and ADP-ribose. Poly-ADP-ribosylation (PARlation) generates a homopolymer of ADP-ribose units called poly-ADP-ribose (PAR) that are catalyzed by

ATP-dependent chromatin-remodelling mechanisms

Chromatin structure can be modified locally by chromatin-remodelling complexes, which transiently dislocate DNA/nucleosome interactions by utilizing the energy of ATP hydrolysis to reposition nucleosomes, modulating accessibility of specific genes to the transcriptional machinery. Chromatin-remodelling complexes are also involved in other processes that require alteration of chromatin structure including DNA repair, DNA synthesis, mitosis and genomic stability. Because of this, ATP-dependent

Epigenetic biomarkers in cancer

DNA methylation constitutes a valuable marker not only for cancer detection but also for prognosis. It has been suggested that the circulating DNA in serum or plasma could be used in the detection of silent tumours through the analysis of patterns of hypermethylated islands, which can be tumour specific. DNA methylation is stable and can be studied by PCR. The pattern of methylation of specific genes may be a molecular marker in thyroid, breast, prostate, gastric and colon carcinomas [224]. A

Concluding remarks

Considerable information has accumulated indicating that aberrant epigenetic gene regulation collaborates with genetic alterations in cancer development [39], [84]. Some epigenetic alterations during cancer development may include: (1) DNA hypermethylation of regulatory sequences of DNA repair enzyme genes, tumour-suppressor genes, hormone receptors, or invasion-metastasis inhibitors; (2) global DNA hypomethylation linked to genomic instability and the activation of metastasis-related genes;

Acknowledgements

We are indebted to the PDT Program (Project 91/29) from the National Council of Science and Technology from Uruguay, the PEDECIBA Program from the University of the Republic (Uruguay) and Mary Curie Fellowship from the European Community.

References (282)

  • S. Pradhan et al.

    Mammalian DNA (cytosine-5) methyltransferases and their expression

    Clin. Immunol.

    (2003)
  • W.A. Burgers et al.

    DNA methyltransferases get connected to chromatin

    Trends Genet.

    (2002)
  • K.E. Bachman et al.

    Dnmt3a y Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin

    J. Biol. Chem.

    (2001)
  • N. Cervoni et al.

    DNA demethylase is a processive enzyme

    J. Biol. Chem.

    (1999)
  • S. Hamm et al.

    On the mechanism of demethylation of 5-methylcytosine in DNA

    Bioorg. Med. Chem. Lett.

    (2008)
  • J.P. Jost et al.

    Mechanisms of DNA demethylation in chicken embryos. Purification and properties of a 5-methylcytosine–DNA glycosylase

    J. Biol. Chem.

    (1995)
  • P.H. Tate et al.

    Effects of DNA methylation on DNA-binding proteins and gene expression

    Curr. Opin. Genet. Dev.

    (1993)
  • M. Nakao

    Epigenetics: interaction of DNA methylation and chromatin

    Genes Dev.

    (2001)
  • R.R. Meehan et al.

    Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs

    Cell

    (1989)
  • N. Cervoni et al.

    Demethylase activity is directed by histone acetylation

    J. Biol. Chem.

    (2001)
  • A.D. Riggs et al.

    X-chromosome inactivation and cell memory

    Trends Genet.

    (1992)
  • M.R. De Baun et al.

    Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith–Wiedemann syndrome with cancer and birth defects

    Am. J. Hum. Genet.

    (2002)
  • P. Szabo et al.

    Maternal-specific footprints at putative CTCF sites in the H19 imprinting control region give evidence for insulator function

    Curr. Biol.

    (2000)
  • K. Delaval et al.

    Epigenetic regulation of mammalian genomic imprinting

    Curr. Opin. Genet. Dev.

    (2004)
  • N. Brockdorff

    X-chromosome inactivation: closing in on proteins that bind Xist RNA

    Trends Genet.

    (2002)
  • D.M. Hellebrekers et al.

    Dual targeting of epigenetic therapy in cancer

    Biochim. Biophys. Acta

    (2007)
  • J.R. Davie

    Inhibition of histone deacetylase activity by butyrate

    J. Nutr.

    (2003)
  • R.D. Kornberg et al.

    Twenty-five years of the nucleosome

    Cell

    (1999)
  • M. Doi et al.

    Circadian regulator CLOCK is a histone acetyltransferase

    Cell

    (2006)
  • N. Ballas et al.

    REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis

    Cell

    (2005)
  • A. Akhtar et al.

    The epigenome network of excellence

    PLoS Biol.

    (2005)
  • G.P. Holmquist et al.

    Chromosome organization and chromatin modification: influence on genome function and evolution

    Cytogenet. Genome Res.

    (2006)
  • M. Rouleau et al.

    Poly(ADP-ribosyl)ated chromatin domains: access granted

    J. Cell Sci.

    (2004)
  • E. Klenova et al.

    Poly(ADP-ribosyl)ation and epigenetics. Is CTCF PARt of the plot?

    Cell Cycle

    (2005)
  • A. Saha et al.

    Chromatin remodelling through directional DNA translocation from an internal nucleosomal site

    Nat. Struct. Mol. Biol.

    (2005)
  • D.J. Fitzgerald et al.

    Reaction cycle of the yeast Isw2 chromatin remodelling complex

    EMBO J.

    (2004)
  • L.M. Merlo et al.

    Cancer as an evolutionary and ecological process

    Nat. Rev./Cancer

    (2006)
  • R.L. Jirtle et al.

    Environmental epigenomics and disease susceptibility

    Nat. Rev./Genet.

    (2007)
  • A.H. Ting et al.

    The cancer epigenome-components and functional correlates

    Genes Dev.

    (2006)
  • M. Ehrlich et al.

    Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells

    Nucleic Acids Res.

    (1982)
  • K.D. Robertson et al.

    DNA methylation: past, present and future directions

    Carcinogenesis

    (2000)
  • M. Szyf

    DNA Methylation and demethylation as targets for anticancer therapy

    Biochemistry

    (2005)
  • A. Bird

    DNA methylation pattern and epigenetic memory

    Genes Dev.

    (2002)
  • M. Rodríguez-Dorantes et al.

    DNA methylation: an epigenetic process of medical importance

    Rev. Invest. Clin.

    (2004)
  • M. Monk et al.

    Temporal and regional changes in DNA methylation in the embryonic, extra-embryonic and germ cell lineages during mouse embryo development

    Development

    (1987)
  • A.P. Bird et al.

    None-methylated CpG-rich islands at the human a globin locus: implications for evolution of the a globin pseudogene

    EMBO J.

    (1987)
  • S.G. Grant et al.

    Mechanisms of X-chromosome regulation

    Annu. Rev. Genet.

    (1988)
  • T. Kafri et al.

    Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line

    Genes Dev.

    (1992)
  • T. Kafri et al.

    Mechanistic aspects of genome-wide demethylation in the preimplantation mouse embryo

    Proc. Natl. Acad. Sci. U.S.A.

    (1993)
  • J.P. Issa et al.

    Epigenetics and human disease

    Nat. Med.

    (1996)
  • Cited by (71)

    View all citing articles on Scopus
    View full text