Harnessing the potential of epigenetic therapy to target solid tumors
Nita Ahuja, … , Hariharan Easwaran, Stephen B. Baylin
Nita Ahuja, … , Hariharan Easwaran, Stephen B. Baylin
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(1):56-63. https://doi.org/10.1172/JCI69736.
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Harnessing the potential of epigenetic therapy to target solid tumors

Abstract

Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer.

Authors

Nita Ahuja, Hariharan Easwaran, Stephen B. Baylin

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Figure 2

Model for initiation of DNA methylation-mediated gene silencing.

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Model for initiation of DNA methylation-mediated gene silencing. (A) Lef...
(A) Left panel: Methylation of CpGs at the borders of CpG islands in normal cells is mediated by the DNMTs as a complex with the HDACs, PRC4 complex (PRC2 component of PcG including SIRT1) with potential involvement of nucleosome remodelers (NuRD). In normal cells, the DNA methylation machinery is restricted from CpG islands, thus protecting these regions from methylation. Right panel: Movement of the repressive complex into the CpG island with stress and associated gene silencing, marked with a red X. However, most genes revert back to the normal cell state. (B) Left panel: A subset of genes with CpG island promoters in embryonic and adult stem cells have both the active (H3K4me3) and inactive (H3K27me3, PcG mark) marks at their promoters, termed “bivalent” marks, in which the genes have a low but poised expression state. Genes that are hypermethylated in cancers frequently have such bivalent marks in the embryonic and adult stem cells. When repetitive insults to cells, such as inflammation, recruit the DNA methylation machinery into the CpG islands of these vulnerable genes, this can initiate abnormal methylation for some of these genes (far right panel). The NuRD complex, a key platform for HDAC1 and -2, may be a part of the complex that maintains silencing of the methylated CpG islands containing genes. Various components of the epigenetic machinery that mediate gene silencing are being targeted already (red ovals), and others are potential targets (green ovals) for cancer therapy.