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" 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.
Lujambio
Amaia
A
Cancer Epigenetics Laboratory and Lung Cancer Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Ropero
Santiago
S
Ballestar
Esteban
E
Fraga
Mario F
MF
Cerrato
Celia
C
Setién
Fernando
F
Casado
Sara
S
Suarez-Gauthier
Ana
A
Sanchez-Cespedes
Montserrat
M
Git
Anna
A
Gitt
Anna
A
Spiteri
Inmaculada
I
Das
Partha P
PP
Caldas
Carlos
C
Miska
Eric
E
Esteller
Manel
M
D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016161:Genes, Retinoblastoma; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000097584:DNA Methyltransferase 3B
D051361:Cyclin-Dependent Kinase 6; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D035683:MicroRNAs; D000097584:DNA Methyltransferase 3B; C509207:MIRN124 microRNA, human; C495911:CDK6 protein, human