1. ¹Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
2. ²Pathology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

Correspondence: Dr H Suzuki, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: hsuzuki@sc.itc.keio.ac.jp

Received 11 December 2008; Revised 23 March 2009; Accepted 18 April 2009; Published online 8 June 2009.

Abstract

Epigenetic therapy using DNA methylation inhibitors and histone deacetylase (HDAC) inhibitors has clinical promise for the treatment of human malignancies. To investigate roles of microRNAs (miRNAs) on epigenetic therapy of gastric cancer, the miRNA expression profile was analysed in human gastric cancer cells treated with 5-aza-2'-deoxycytidine (5-Aza-CdR) and 4-phenylbutyric acid (PBA). miRNA microarray analysis shows that most of miRNAs activated by 5-Aza-CdR and PBA in gastric cancer cells are located at Alu repeats on chromosome 19. Analyses of chromatin modification show that DNA demethylation and HDAC inhibition at Alu repeats activates silenced miR-512-5p by RNA polymerase II. In addition, activation of miR-512-5p by epigenetic treatment induces suppression of Mcl-1, resulting in apoptosis of gastric cancer cells. These results suggest that chromatin remodeling at Alu repeats plays critical roles in the regulation of miRNA expression and that epigenetic activation of silenced Alu-associated miRNAs could be a novel therapeutic approach for gastric cancer.