Epigenetic regulation of microRNA expression in colorectal cancer.
In the last years, microRNAs (miRNA) have emerged as new molecular players involved in carcinogenesis. Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown. To identify tumor-supressor miRNAs silenced through aberrant epigenetic events in colorectal cancer (CRC), we used a sequential approach. We first identified 5 miRNAs down-regulated in patient with colorectal cancer samples and located around/on a CpG island. Treatment with a DNA methyltransferase inhibitor and a HDAC inhibitor restored expression of 3 of the 5 microRNAs (hsa-miR-9, hsa-miR-129 and hsa-miR-137) in 3 CRC cell lines. Expression of hsa-miR-9 was inversely correlated with methylation of their promoter regions as measure by MSP and bisulphate sequencing. Further, methylation of the hsa-miR-9-1, hsa-miR-129-2 and hsa-miR-137 CpG islands were frequently observed in CRC cell lines and in primary CRC tumors, but not in normal colonic mucosa. Finally, methylation of hsa-miR-9-1 was associated with the presence of lymph node metastasis. In summary, our results aid in the understanding of miRNA gene regulation showing that aberrant DNA methylation and histone modifications work together to induce silencing of miRNAs in CRC.
Bandres
Eva
E
Division of Oncology, Laboratory of Pharmacogenomics, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain. ebandres@unav.es
Agirre
Xabier
X
Bitarte
Nerea
N
Ramirez
Natalia
N
Zarate
Ruth
R
Roman-Gomez
Jose
J
Prosper
Felipe
F
Garcia-Foncillas
Jesus
J
D000107:Acetylation; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D035683:MicroRNAs; D010654:Phenylbutyrates; C036032:3-phenylbutyric acid; D006655:Histone Deacetylases; D001374:Azacitidine