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.
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References
Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R et al. (2005). Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122: 553–563.
Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O et al. (2005). Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 37: 766–770.
Borchert GM, Lanier W, Davidson BL . (2006). RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13: 1097–1101.
Calin GA, Croce CM . (2006a). MicroRNA signatures in human cancers. Nat Rev Cancer 6: 857–866.
Calin GA, Croce CM . (2006b). MicroRNAs and chromosomal abnormalities in cancer cells. Oncogene 25: 6202–6210.
Esteller M . (2002). CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21: 5427–5440.
Gal-Yam EN, Saito Y, Egger G, Jones PA . (2008). Cancer epigenetics: modifications, screening, and therapy. Annu Rev Med 59: 267–280.
Kondo Y, Issa JP . (2003). Enrichment for histone H3 lysine 9 methylation at Alu repeats in human cells. J Biol Chem 278: 27658–27662.
Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW . (1993). MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci USA 90: 3516–3520.
Krajewska M, Fenoglio-Preiser CM, Krajewski S, Song K, Macdonald JS, Stemmerman G et al. (1996). Immunohistochemical analysis of Bcl-2 family proteins in adenocarcinomas of the stomach. Am J Pathol 149: 1449–1457.
Liu WM, Maraia RJ, Rubin CM, Schmid CW . (1994). Alu transcripts: cytoplasmic localisation and regulation by DNA methylation. Nucleic Acids Res 22: 1087–1095.
Maeta Y, Tsujitani S, Matsumoto S, Yamaguchi K, Tatebe S, Kondo A et al. (2004). Expression of Mcl-1 and p53 proteins predicts the survival of patients with T3 gastric carcinoma. Gastric Cancer 7: 78–84.
Ochiai A, Yasui W, Tahara E . (1985). Growth-promoting effect of gastrin on human gastric carcinoma cell line TMK-1. Jpn J Cancer Res 76: 1064–1071.
Oei SL, Babich VS, Kazakov VI, Usmanova NM, Kropotov AV, Tomilin NV . (2004). Clusters of regulatory signals for RNA polymerase II transcription associated with Alu family repeats and CpG islands in human promoters. Genomics 83: 873–882.
Parkin DM . (2001). Global cancer statistics in the year 2000. Lancet Oncol 2: 533–543.
Saito Y, Jones PA . (2006). Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5: 2220–2222.
Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA et al. (2006). Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9: 435–443.
Shigemasa K, Katoh O, Shiroyama Y, Mihara S, Mukai K, Nagai N et al. (2002). Increased MCL-1 expression is associated with poor prognosis in ovarian carcinomas. Jpn J Cancer Res 93: 542–550.
Suzuki H, Seto K, Mori M, Suzuki M, Miura S, Ishii H . (1998). Monochloramine induced DNA fragmentation in gastric cell line MKN45. Am J Physiol 275: G712–G716.
Taniai M, Grambihler A, Higuchi H, Werneburg N, Bronk SF, Farrugia DJ et al. (2004). Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells. Cancer Res 64: 3517–3524.
Wacheck V, Cejka D, Sieghart W, Losert D, Strommer S, Crevenna R et al. (2006). Mcl-1 is a relevant molecular target for antisense oligonucleotide strategies in gastric cancer cells. Cancer Biol Ther 5: 1348–1354.
Wu L, Fan J, Belasco JG . (2006). MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci USA 103: 4034–4039.
Yekta S, Shih IH, Bartel DP . (2004). MicroRNA-directed cleavage of HOXB8 mRNA. Science 304: 594–596.
Yoo CB, Jones PA . (2006). Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5: 37–50.
Zangemeister-Wittke U, Huwiler A . (2006). Antisense targeting of Mcl-1 has therapeutic potential in gastric cancer. Cancer Biol Ther 5: 1355–1356.
Zhou P, Qian L, Kozopas KM, Craig RW . (1997). Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions. Blood 89: 630–643.
Acknowledgements
The authors are grateful to Dr Robert Roeder at Rockefeller University for providing antibody to Pol III. This work was supported by a Grant-in-Aid for Scientific Research C from the Japan Society for the Promotion of Science (JSPS) (19599024, to Y.S.) and a Grant-in-Aid for Exploratory Research from JSPS (19659057, to HS).
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Saito, Y., Suzuki, H., Tsugawa, H. et al. Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells. Oncogene 28, 2738–2744 (2009). https://doi.org/10.1038/onc.2009.140
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DOI: https://doi.org/10.1038/onc.2009.140
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