Epigenetic Silencing of Tumor Suppressor Genes
Inventors: Michael Witcher and Beverly Emerson
Potential Uses: Drug Discovery and Development, Oncology
Epigenetic silencing of tumor suppressor genes occurs through loss of CTCF binding and chromatin boundaries
A model for aberrant epigenetic silencing of the p16 locus through dissociation of PARlated CTCF protein and specific cofactors, resulting in destabilization of an upstream chromatin boundary and the spreading of adjacent heterochromatin into the active p16 gene.
A widespread characteristic of most human malignancies is aberrant transcriptional silencing of tumor suppressor genes by defective epigenetic processes. This is often an early event in tumorigenesis that persists in late-stage cancers. Because this type of gene silencing occurs without apparent DNA mutation or deletion, the possibility exists that gene function can be restored through reversal of the defective epigenetic programming. Currently, the mechanism of epigenetic silencing is undefined, and only non-specific DNA demethylating agents and HDAC inhibitors are used to reverse gene silencing.
We have investigated the basis for aberrant silencing of one of the most frequent targets of inactivation in human cancers, the p16 gene, which is a critical regulator of cell cycle arrest and senescence. Our approach focused on the chromosomal locus that the p16 gene resides in, rather than on the degregulated promoter. This led to the discovery that a domain boundary upstream from the p16 transcriptional start site that is present in normal cells, is missing in human breast cancer cells. This is because the multifunctional protein, CTCF binds near this boundary in normal, p16 expressing cells, but is dissociated in cancerous, non-expressing cells. This discovery supports the hypothesis that a common mechanism may account for widespread occurrence of epigenetic silencing in human cancers: destabilization of specific chromosomal boundaries.
Patent Status: U.S. Patent Application and PCT Application filed April 2009
Publications: Molecular Cell 34: 271-284 (May 2009)
Press Release: Fences Make Good Neighbors
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