Transcription factors of the Ikaros gene family are essential for cellular differentiation in the lymphoid branch of the hematopoietic system, and genetic defects in this gene family are implicated in hematologic malignancies.
Esteban Ballestar, Ph.D., leader of the chromatin and disease group at the Bellvitge Biomedical Research Institute in Barcelona, and colleagues recently examined whether the Ikaros gene is also inactivated by aberrant methylation.
“We found very little methylation in the promoters of these transcription factors in leukemias and lymphomas,” said Dr. Ballestar. However, the investigators made an unexpected observation.
“We actually noticed aberrant hypermethylation in a different type of malignant tumor—colorectal cancer,” he continued.
Dr. Ballestar and colleagues recently reported Ikaros promoter hypermethylation in all colorectal cancer cell lines and in over 60% of the primary colorectal cancers examined, and also found several deregulated Ikaros targets that might be important for colorectal cancer progression.
“The possibilities offered by high-throughput enabled us to conduct screening to see whether methylation changes are focal or involve larger chromosomal regions. We saw that this hypermethylation occurred in context of hypermethylation within a larger region,” explained Dr. Ballestar.
CpG hypermethylation occured in context of aberrant hypermethylation within a 2 megabase chromosomal region centered around the Ikaros gene, a phenomenon known as long-range epigenetic silencing, and this study provided the first piece of evidence establishing the functional importance of long-range epigenetic silencing in cancer, as it results in deregulation of Ikaros downstream targets.
Furthermore, the authors found a correlation between the degree of Ikaros hypermethylation and tumor malignancy. The percentage of Ikaros methylation increased from approximately 30% in the less aggressive Dukes stage A tumors to 81% in the more malignant stage D tumors, a finding with important clinical implications.
“It will not be too long until we can see antisense molecules directed against microRNAs being used in the clinic as anticancer therapeutics,” predicted Frank J. Slack, Ph.D., professor of molecular, cellular, and developmental biology at Yale University.
MicroRNAs, a class of small RNA molecules that fulfill important functions during differentiation and disease, regulate gene expression at the post-transcriptional level and emerge as an exciting development in the field of epigenetics. Certain microRNAs function as oncogenes, while others are tumor-suppressor genes. One of the most interesting microRNAs, miR-21, is overexpressed in most tumor types analyzed to date, a finding that promises therapeutic applications.
“The most important implication is the possibility of finding ways to target microRNAs such as miR-21 with antisense molecules or drugs, and this might become a very useful strategy in anticancer therapeutics,” pointed out Dr. Slack.
Recently, Dr. Slack and colleagues generated a genetically engineered mouse that conditionally expresses miR-21. This animal model showed that miR-21 overexpression leads to a pre-B malignant lymphoid-like phenotype, and revealed its in vivo importance for all stages of tumor development including initiation, maintenance, and survival.