Genetic unmasking of an epigenetically silenced microRNA in human cancer cells

The mechanisms underlying microRNA (miRNA) disruption in human disease are poorly understood. In cancer cells, the transcriptional silencing of tumor suppressor genes by CpG island promoter hypermethylation has emerged as a common hallmark. We wondered if the same epigenetic disruption can "hit...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2007-02, Vol.67 (4), p.1424-1429
Main Authors: LUJAMBIO, Amaia, ROPERO, Santiago, SPITERI, Inmaculada, DAS, Partha P, CALDAS, Carlos, MISKA, Eric, ESTELLER, Manel, BALLESTAR, Esteban, FRAGA, Mario F, CERRATO, Celia, SETIEN, Fernando, CASADO, Sara, SUAREZ-GAUTHIER, Ana, SANCHEZ-CESPEDES, Montserrat, GITT, Anna
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Cell Transformation, Neoplastic - genetics
Colonic Neoplasms - enzymology
Colonic Neoplasms - genetics
Cyclin-Dependent Kinase 6 - genetics
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases - deficiency
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA Methylation
DNA Methyltransferase 3B
Down-Regulation
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Retinoblastoma
HCT116 Cells
Humans
Medical sciences
MicroRNAs - genetics
MicroRNAs - metabolism
Pharmacology. Drug treatments
Tumors
Up-Regulation
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Summary:The mechanisms underlying microRNA (miRNA) disruption in human disease are poorly understood. In cancer cells, the transcriptional silencing of tumor suppressor genes by CpG island promoter hypermethylation has emerged as a common hallmark. We wondered if the same epigenetic disruption can "hit" miRNAs in transformed cells. To address this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in combination with a miRNA expression profiling. We have observed that DNA hypomethylation induces a release of miRNA silencing in cancer cells. One of the main targets is miRNA-124a, which undergoes transcriptional inactivation by CpG island hypermethylation in human tumors from different cell types. Interestingly, we functionally link the epigenetic loss of miRNA-124a with the activation of cyclin D kinase 6, a bona fide oncogenic factor, and the phosphorylation of the retinoblastoma, a tumor suppressor gene.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-06-4218