Reversal of Aberrant Cancer Gene Silencing By Inhibition of SIRT1
The class III histone deactylase (HDAC), SIRT1, has cancer relevance because it regulates lifespan in multiple organisms, down-regulates p53 function through deacetylation, and is linked to polycomb gene silencing in Drosophila. JHU inventors have shown that SIRT1 localizes to promoters of several aberrantly silenced tumor suppressor genes (TSGs) in which CpG islands are densely hypermethylated, but not to these same promoters in cell lines in which the promoters are not hypermethylated and the genes are expressed. Heretofore, only type I and II HDACs had been tied to TSG silencing. Inhibition of these enzymes alone fails to re-activate the genes unless DNA methylation is first inhibited. In contrast, inhibition of SIRT1 by pharmacologic, dominant negative, and siRNA (small interfering RNA)�mediated inhibition in breast and colon cancer cells causes increased H4-K16 and H3-K9 acetylation at endogenous promoters and gene re-expression despite full retention of promoter DNA hypermethylation. Furthermore, SIRT1inhibition affects key phenotypic aspects of cancer cells. JHU inventors have identified a new component of epigenetic TSG silencing that may potentially link some epigenetic changes associated with aging with those found in cancer, and provide new directions for therapeutically targeting these important genes for re-expression. Description (Set) Proposed Use (Set) There is currently much interest in developing strategies to reverse abnormal gene silencing in cancer especially that associated with genes for which promoters have aberrant DNA methylation, as a cancer therapy and prevention strategy. This invention reveals a role for a completely separate class of HDAC�s, the class 3 HDAC�s or sirtuins. The fact that inhibition of the class 3 HDAC, SIRT1, can reverse the gene silencing without changing the promoter DNA methylation, and that it can synergize with the above outlined drugs to do so, provides the potential for novel strategies of single or combination agents for cancer therapy.Inventor(s): Pruitt, Kevin
Type of Offer: Licensing
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