Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells.
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.
Saito
Y
Y
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Suzuki
H
H
Tsugawa
H
H
Nakagawa
I
I
Matsuzaki
J
J
Kanai
Y
Y
Hibi
T
T
D020087:Alu Elements; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D002888:Chromosomes, Human, Pair 19; D019175:DNA Methylation; D004257:DNA Polymerase II / Q000502:physiology; D004258:DNA Polymerase III / Q000502:physiology; D000077209:Decitabine; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010654:Phenylbutyrates / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D056572:Histone Deacetylase Inhibitors; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010654:Phenylbutyrates; D019253:Proto-Oncogene Proteins c-bcl-2; D000077209:Decitabine; C075773:4-phenylbutyric acid; D004257:DNA Polymerase II; D004258:DNA Polymerase III; D001374:Azacitidine