Recent advances in epigenetic therapy are promising, but their mechanisms of action and impact elsewhere in the epigenome remain a bit of a mystery. Armed with microarrays and ChIP assays, a talented team of Japanese researchers took a closer look at these approaches and found DNA methylation inhibitors and histone deacetylase (HDAC) inhibitors kill gastric cancer cells by waking up silenced miRNAs nestled near Alu repeats. Once activated, these miRNAs are ready to do battle, silencing oncogenes and driving cancer cells into apoptosis.
The researchers, from Keio University School of Medicine and the National Cancer Center Research Institute, found that epigenetic treatment activated the expression of hundreds of miRNAs in gastric cancer cells. Most of the highly activated miRNAs were near Alu repeats on chromosome 19. Although previous work has indicated that Pol III transcribes Alu-associated miRNAs, the team found that Pol II was the key player behind the epigenetic activation of the miRNAs including miR-512-5p, one of the highly expressed miRNAs.
The researchers go on to show that DNA methylation inhibitors and HDAC inhibitors remodel chromatin at Alu repeats, driving miR-512-5p expression, which suppresses Mcl-1, an oncogene that keeps cancer cells chugging along. The data suggest that activation of Alu-associated miRNAs with epigenetic therapies could treat, or even prevent, gastric cancer. See for yourself at Oncogene, June 2009.