Epigenetic Activation of Tumor Suppressor MicroRNAs in Human Cancer Cells

Saito, Yoshimasa; Jones, Peter M.

doi:10.4161/cc.5.19.3340

Cited by 254 publications

(165 citation statements)

References 23 publications

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“…26 The observation that miRNA genes can become aberrantly methylated in tumors now adds an additional layer of complexity to the effects of epigenetic deregulation in cancer. 27 The functional consequences of altered miRNA gene methylation on tumorigenesis can be illustrated by results from the studies discussed previously. Epigenetic reactivation of miR-127 resulted in downregulation of the BCL6 proto-oncogene, a transcriptional repressor that has been shown to be involved in p53 regulation.…”

Section: Functional Consequences Of Altered Mirna Gene Methylation Inmentioning

confidence: 99%

Methylation of Human MicroRNA Genes in Normal and Neoplastic Cells

et al. 2007

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Section: Functional Consequences Of Altered Mirna Gene Methylation Inmentioning

confidence: 99%

Methylation of Human MicroRNA Genes in Normal and Neoplastic Cells

et al. 2007

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“…Recent studies have indicated that aberrant expression of miRNAs contributes to the initiation and progression of human malignancies (Calin and Croce, 2006a, b). We have recently shown that some miRNAs are located near CpG islands and that expression of these miRNAs is regulated by alterations in DNA methylation and histone modification on their CpG islands (Saito and Jones, 2006;.…”

Section: Introductionmentioning

confidence: 99%

Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells

et al. 2009

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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 0 -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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“…We hypothesized that one mode of transcriptional silencing of microRNAs may be epigenetic mechanisms related to the aberrant DNA methylation of 5 0 -regulatory regions, as has been observed for many 'conventional' tumor suppressor genes (Toyota et al, 1999;Kondo and Issa, 2004;Kim et al, 2006). In fact, examples of DNA methylation-based regulation of microRNA genes by proximal CpG islands have been recently described (Saito and Jones, 2006;Brueckner et al, 2007;Lujambio et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer

et al. 2008

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MicroRNAs are small, non-coding RNAs that influence gene regulatory networks by post-transcriptional regulation of specific messenger RNA targets. MicroRNA expression is dysregulated in human malignancies, frequently leading to loss of expression of certain microRNAs. We report that expression of hsa-miR-342, a microRNA encoded in an intron of the gene EVL, is commonly suppressed in human colorectal cancer. The expression of hsa-miR-342 is coordinated with that of EVL and our results indicate that the mechanism of silencing is CpG island methylation upstream of EVL. We found methylation at the EVL/hsa-miR-342 locus in 86% of colorectal adenocarcinomas and in 67% of adenomas, indicating that it is an early event in colorectal carcinogenesis. In addition, we observed a higher frequency of methylation (56%) in histologically normal colorectal mucosa from individuals with concurrent cancer compared to mucosa from individuals without colorectal cancer (12%), suggesting the existence of a 'field defect' involving methylated EVL/hsa-miR-342. Furthermore, reconstitution of hsa-miR-342 in the colorectal cancer cell line HT-29 induced apoptosis, suggesting that this microRNA could function as a proapoptotic tumor suppressor. In aggregate, these results support a novel mechanism for silencing intronic microRNAs in cancer by epigenetic alterations of cognate host genes.

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Epigenetic Activation of Tumor Suppressor MicroRNAs in Human Cancer Cells

Cited by 254 publications

References 23 publications

Methylation of Human MicroRNA Genes in Normal and Neoplastic Cells

Methylation of Human MicroRNA Genes in Normal and Neoplastic Cells

Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells

Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer

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