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Feb 1, 2012 (Vol. 32, No. 3)

Exploring the Role of Epigenetics

  • Aberrant Methylation

    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.

  • Oncogene Addiction

    Click Image To Enlarge +
    The mouse on the left has an enlarged lymph node (lymphadenopathy; white arrow) caused by miR-21-induced lymphoma. The same mouse, shown on the right three days following treatment to reduce miR-21 levels, shows no signs of lymphoma. [Yale University]

    These findings illustrated that miR-21 is an oncogene, adding to previous reports that found certain malignant tumors to be dependent on one or a few genes that maintain the cancer phenotype, a phenomenon known as “oncogene addiction.”

    “Oncogene addiction itself is one of the reasons why targeted drug therapies show at least some efficacy in patients at the moment, and we are currently testing whether microR-21 is also involved in other types of cancer besides lymphoma, and whether other microRNAs are also oncogenes and are also subject to oncogene addiction, just like miR-21,” according to Dr. Slack.

  • Cancer Staging and Treatment

    The presence of metastases has important implications for cancer staging and treatment, and metastatic dissemination represents the leading cause of cancer mortality. Historically metastases have been associated with a dire prognosis.

    However, this paradigm was challenged in the mid 1990s, with a seminal observation made by Samuel Hellman, M.D., and Ralph R. Weichselbaum, M.D., from the University of Chicago School of Medicine, who introduced the concept of oligometastases.

    Oligometastases represent a potentially curable state during the evolution of some malignant tumors, intermediate between absent and widespread metastases. This was defined in the original study by the presence of five or fewer cumulative metastatic disseminations.

    “We set out to explore the biological basis that helps understand oligometastasis,” said Dr. Weichselbaum. In collaboration with Yves Lussier, M.D., at the University of Chicago, Dr. Weichselbaum’s group defined, by performing a bioinformatics analysis on differentially expressed microRNAs from histological cancer samples with oligo- and poly-metastatic dissemination, a prioritized list of several microRNAs associated with oligometastasis.

    “One of the highest ranking and most interesting candidates that we found is microRNA-200c,” said Dr. Weichselbaum. This microRNA, which suppresses ZEB1 and ZEB2, its direct targets that transcriptionally suppress E-cadherin, prevents the epithelial-to-mesenchymal transition and is important for maintaining epithelial cell identity.

    “We are working to try to validate this finding on a dataset of colon to liver cancer and on a variety of tumors metastasizing to the lung,” he continued.

    The involvement of microRNA-200c in oligometastasis is the first time that the biological basis for the differences between oligometastatic and polymetastatic states is explained and has important therapeutic implications.

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