Chemistry Reference
In-Depth Information
inducing apoptosis in a wide variety of cells, because
of its induction of oxidative stress (Aydin
et al.
, 2003;
Bagchi
et al.
, 2000; Jimi
et al.
, 2004; Poliandri
et al.
,
2003; Shin
et al.
, 2004; Tzirogiannis
et al.
, 2003; Watjen
et al.
, 2002). Cd has also been shown to inhibit DNA
repair (Buchko
et al.
, 2000; Hartwig
et al.
, 2002a; 2002b;
Waisberg
et al.
, 2003; Zharkov and Rosenquist, 2002).
covalently attached to the C-5 position of cytosine by
a family of DNA-methyltransferases (DNMTs). DNA
methylation plays an important role in the regulation of
gene expression and the silencing of repeat elements in
the genome (Feinberg, 2004). The deregulation of DNA
methylation mainly includes hypomethylation, which
leads to oncogene activation and chromosomal insta-
bility, and hypermethylation, which leads to the silenc-
ing of tumor suppressor genes (Jones and Laird, 1999).
5 EPIGENETIC EFFECTS
OF METAL COMPOUNDS
5.2.2 Histone Modifi cations
Histone modifi cations occur at the N-terminal and
the C-terminal of histone tails, and include, but are not
limited to, acetylation, methylation, phosphorylation,
ubiquitination, sumoylation, and ADP-ribosylation.
These modifi cations play a pivotal role in regulating
gene transcription and other chromatin-associated
processes (Jenuwein and Allis, 2001).
5.1 Introduction
Epigenetics involves a heritable change in gene expres-
sion that does not result in a change of DNA sequence
(Riddihough and Pennisi, 2001). Recent research has
established that epigenetic changes play an important
role in tumorigenesis (Feinberg, 2004). The major epi-
genetic changes taking place during the development
of cancer include aberrant DNA methylation and his-
tone modifi cations (Momparler, 2003). These epigenetic
events can act in concert to silence the expression of
genes that suppress tumorigenesis or activate oncogenes
(Feinberg, 2004). Metal compounds, such as As, Cd, and
Ni, have been shown to affect levels of DNA methyla-
tion and/or histone modifi cations at both global and
gene-specifi c levels. In the fi rst part of this section, DNA
methylation and specifi c histone modifi cations will be
introduced. The effects of metal compounds, mainly,
As, Cd, and Ni, on these epigenetic parameters will be
reviewed, and at the end of this section, we will include
a summary table of epigenetic events affected by met-
als for easy future reference (Table 1). Because this is
an emerging fi eld of study, we have spent considerable
time on this part of the chapter.
5.2.2.1 Histone Acetylation
All four-core histones can be reversibly acetylated
at defi ned lysine residues on their N-terminal tails by
histone acetyltransferases (HATs) and deacetylated by
histone deacetylases (HDACs) (Klochendler-Yeivin
and Yaniv, 2001). In general, hyperacetylation contrib-
utes to the formation of an “open” chromatin state
and permits access of transcription factors to DNA.
In contrast, hypoacetylation contributes to a “closed”
chromatin and transcription repression (Turner, 2000).
Lysine acetylation is believed to neutralize part of the
positively charged histone tails, which may weaken the
interactions between histone-DNA (Grant
et al.
, 1998),
histone-histone (Fletcher and Hansen, 1996), nucleo-
some-nucleosome (Lutter
et al.
, 1992; Norton
et al.
, 1989;
1990), or the interaction between nucleosomes and other
nonhistone chromosomal proteins (Hecht
et al.
, 1995).
As a result, it may destabilize higher order chromatin
organization and facilitate the access of transcription
factors to nucleosomal DNA, resulting in enhanced
DNA transcription. In addition, proteins with histone
acetyltransferase (HAT) activity have been shown to
be coactivators of transcription, whereas those with
histone deacetyltransferase (HDAC) activity are core-
pressors of transcription (Lehrmann
et al.
, 2002). The
balance between acetylation and deacetylation of his-
tones plays an important regulatory role in gene tran-
scription. Deregulation of this balance has been linked
to the progression of cancers and diverse human disor-
ders (Lehrmann
et al.
, 2002; Timmermann
et al.
, 2001).
5.2 Epigenetic Events in the Development
of Cancer
5.2.1 DNA Methylation
DNA methylation occurs at the cytosine residue of
CpG dinucleotides of DNA, in which a methyl group
is transferred from S-adenosyl-methionine (SAM) and
TABLE 1
Summary of the Epigenetic Events
Affected by Metals
Epigenetic events
Classifi cation
Metal inducers
DNA methylation
Hypomethylation
As, Cd, Ni
Hypermethylation
As, Cd, Ni
Histone modifi cations
Acetylation
As, Ni
5.2.2.2 Histone Methylation
Histone methylation occurs predominantly on
histones H3 and H4. There are two types of histone
Methylation
Ni
Phosphorylation
As
