Full Professor,
Ph.D., Hebrew Univ. (Jerusalem)
Room: MCMED
1309/1310
Phone: 398-7107
Fax: 398-6690
E-Mail:
mszyf@pharma.mcgill.ca
General Interests of the laboratory:
3. Cancer is an epigenetic disease
4. Therapeutic implications of the epigenome on anticaner therapy
What is
the epigenome?
While genomic
information is uniform in the different cells of complex organisms, the
epigenome controls the differential expression of genes in specific cells. The
programming of gene expression profiles is therefore dependent on the epigenome.
The epigenome is composed of two modules, a component that is part of the
covalent structure of DNA, methylated cytosines located in the dinucleotide
sequence CG and a noncovalent module. Our understanding of the noncovalent
module of the epigenome the chromatin and its associated chromatin modifying and
remodeling activities is rapidly expanding in recent years (Strahl and Allis,
2000). It is now becoming clear that modifications of histones and their tails
by acetylation, phosphorylation, and methylation plays an important role in
determining the positioning of nucleosomes on DNA and the compactness of
chromatin. Chromatin structure determines the state of activity of genes by
gating the access of the transcription machinery to transcriptional regulatory
regions. Chromatin structure plays a role in other genomic activities such as
recombination and repai. Changes in chromatin structure play an important role
in the silencing of certain genes in cancer and histone deacetylase inhibitors
have demonstrated anticancer effect.
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What
is DNA methylation?
In addition to this flexible and dynamic
module of the epigenome, which is associated with the genome but is not part of
its covalent structure, the genome is covalently modified by addition of a
methyl group at the 5th position of the cytosine ring. Since the methyl group is
connected to DNA by a strong chemical bond, it is considered a stable and fixed
mark. The vast majority of methylated cytosines in vertebrate genomes are found
in the dinucleotide sequence CG. Not all CG dinucleotide sequences are
methylated, different CGs are methylated in different tissues creating a pattern
of methylation that is gene and tissue specific. Thus, there is a good
correlation between the state of activity of genes and lack of methylation of
CGs in their regulatory regions (Razin and Riggs, 1980). Remarkably, there is
also a tight correlation between the chromatin structure and the status of DNA
methylation (Razin and Cedar, 1977). We propose that the DNA methylation pattern
is steady state equilibrium of DNA methylation and demethylation reactions. DNA
methylation is catalyzed by DNA methyltransferase enzyme and demethylation
catalyzed by demethylase enzymes. The DNA methylation reaction is stimulated by
inactive chromatin and demethylation by active chromatin. Thus the direction of
the DNA methylation reaction is determined by chromatin structure.
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Cancer is
an epigenetic disease
It is now clear
that cancer is an epigenetic disease. In most tumors the DNA methylation pattern
is defective. Vast regions of the genome lose their methylation while specific
regions are heavily methylated.
Understanding the mechanisms that link chromatin structure and DNA methylation
are extremely important for unraveling the possible mechanisms responsible for
the DNA methylation pattern in normal tissues, possible physiological
alterations of DNA methylation patterns throughout life and during the aging
process, and its aberration in cancer. Before we are able to properly target DNA
methylation in cancer therapy we ought to understand which of the changes in the
DNA methylation machinery and DNA methylation pattern are causal for cancer and
which are a consequence of the transformation process.
My laboratory is interested in
understanding the links between chromatin, DNA methylation and cancer therapy.
We want to understand what mechanisms define the DNA methylation pattern and why
is the DNA methylation pattern tightly correlated with chromatin structure. Our
working hypothesis is that both the DNA methylation and demethylation
machineries are directed by chromatin structure and that both are defective in
cancer. We want to understand how chromatin directs DNA methyltransferase and
demethylase and how why they are involved in cancer and metastasis.
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Therapeutic implications of the epigenome on anticancer
therapy
Inhibition of the main DNA methylation
enzyme DNMT1 and the demethylase/ MBD2 results in a marked anticancer effect and
has potential in anticancer therapy. We developed antisense and direct
inhibitors of DNMT1 with demonstrated preclinical anticancer effect. A DNMT1
antisense molecule is currently in clinical trials (directed by MethylGene
Inc.). Inhibition of MBD2/demethylase also showed anticancer activity in
preclinical studies. We are interested in identifying under members of the
epigenome that might serve as anticancer targets.
Discussion of our model on the anticancer
potential of DNA methylation and demethylation inhibitors will be found in: {Szyf
M., 1994, Trends Pharmacol Sci, 15(7), 233-8, Szyf M., 1996, Pharmacol Ther,
70(1), 1-37; Szyf M., 1998, Cancer Metastasis Rev, 17(2), 219-31, Szyf M. et
al., 2000, Ann N Y Acad Sci, 910, 156-74; discussion 175-7, Szyf Moshe, 2000,
Current Drug Targets, 1(1), 101-118, Szyf M., 2001, Trends Pharmacol Sci, 22(7),
350-354., Szyf M and Detich N, 2001, Prog Nucleic Acid Res Mol Biol, 69, 47-79}
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