DEPARTMENT OF
COMPARATIVE PATHOBIOLOGY
Kenneth P. Nephew, Ph.D.
Professor, Department of Cellular and Integrative Physiology
Adjunct Professor of Obstetrics and Gynecology
“An Epigenetic Approach To Understanding The Pathobiology
Of Cancer”
Thursday, October 25, 2007
10:30 am
ABSTRACT:
The term epigenetics refers
to heritable DNA modifications that occur outside of primary base-coding
sequences. The most common of these is
methylation of cytosine, usually located within the dinucleotide CpG, catalyzed
by enzymes known as DNA methyltransferases (DNMTs). CpG islands, regions of DNA
with a high GC content and typically located near the promoter of a gene, are
usually unmethylated in normal cells.
However, it has now been well established that CpG islands often become
hypermethylated and transcriptionally silenced in tumors, despite an overall
global decrease in DNA methylation (i.e.,
global hypomethylation) in the tumor. Other commonly occurring epigenetic
modifications within silenced genes are hypoacetylation and methylation of
their associated histones. A number of
histone lysines have been discovered as methylated; these modifications can be
transcriptionally activating or repressing, depending on the specific residue.
The comprehensive collection of genome-wide epigenetic phenomena,
DNA-methylation patterns and chromatin modifications, is called the
epigenome. Furthermore, most if not all
human cancers are at least partially associated with epigenetic dysregulation
of gene expression, forming a rational basis for future treatment strategies
designed to alter this fundamental processes in cancer. We have investigated
the role of the epigenome in the pathobiology of ovarian and breast cancer and have identified potential
epigenetic biomarkers for these diseases. Unlike genetic changes, the
epigenetic changes in cancer are potentially reversible, and the ability to reactivate epigentically-silenced tumor suppressor genes
and key control pathways and reverse the cancer cell phenotype is a promising
strategy. Epigenetic drugs,
including demethylating agents and histone deacetylase inhibitors, can be used singly or in combination with currently available cancer
chemotherapies. An approach we
are taking in the clinic is to use a demethylating agent to re-sensitize
drug-resistant cancer cells to standard chemotherapeutic approaches. A new opportunity in cancer research is that
many cancers are now believed to contain a small population of “cancer stem
cells” responsible for growing an entire tumor. While conventional cancer
chemotherapies kill most of the cells in a tumor, they may miss these cancer
stem cells, allowing the tumor to re-grow. Epigenetic changes may be a way to
characterize cancer stem cells, and new drugs that alter those DNA structural
changes may represent a new type of therapy against those cells, allowing
complete killing of the tumor.