RUNX3 and Retinoic Acid Receptor β DNA Methylation as Novel Targets for Gastric Cancer Therapy

Methylation of CpG islands in many tumor suppressor genes with or without changes in histone acetylation is an important mechanism of gene silencing during the development of different types of cancer. There are at least two types of CpG island methylator phenotypes in intestinal- and diffuse -types of gastric cancer. Hypermethylation of the p16 and of hMLH1 promoters is preferentially found in intestinal-type gastric carcinoma, while concordant hypermethylation of the CDH1 and RAR-β2 promoters is predominantly associated with diffuse-type gastric carcinoma. Loss of RUNX3 and pS2 expression by promoter methylation is a common event in both types of gastric carcinoma. These results suggest that CpG island methylator phenotype may be one of the major pathways responsible for the development of the two types of gastric cancer and that RUNX3 and RAR-β2 may provide potential targets for therapeutic intervention to treat gastric cancer. Reactivation of RUNX3 and RAR-β2 by demethylating agents [e.g., 5-aza-2-deoxycytidine (DAC)] and histone deacetylase (HDAC) inhibitors [e.g., suberoylanilide hydroxamic acid (SAHA)] may be clinical useful for gastric cancer therapy with retinoids. This article will provide an overview of the molecular machinery that underlies two types of gastric cancer and focus on HDAC inhibitors that are potentially effective anticancer agents, not only for breast and prostate cancers but also for gastric cancer.