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The role of the Jumonji 2 (JMJD2) Histone Demethylases in Cell Proliferation and Cancer

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DNA is wrapped around histone proteins forming an organized structure called chromatin. Post-translational modifications of histones are crucial for transcriptional regulation, as well as for maintenance of genomic stability and for cell proliferation and differentiation. Genes encoding histone-modifying enzymes are thus commonly found deregulated in human cancers.

Others and we recently showed that the Jumonji 2 (JMJD2) proteins are histone demethylases specific for tri- and di-methylated lysine 9 and lysine 36 on histone H3 (H3K9 and H3K36). Methylation of H3K9 is associated with heterochromatic areas of the genome, which are condensed and transcriptionally inactive. Methylated H3K36 is, on the other hand, primarily detected within the transcribed regions of active genes. Several lines of evidence indicate that the JMJD2 demethylases could be involved in malignant transformation. The expression of the JMJD2 histone demethylases is highly elevated in a subset of human cancers, and knockdown of JMJD2C (a.k.a. Gene Amplified in Squamous cell Carcinoma 1 (GASC1)) retards growth of tumor cell lines. Furthermore mice deficient for one of the key enzymes responsible for H3K9 di- and tri-methylation are tumor prone.

To elucidate the role of the JMJD2 histone demethylases in cell proliferation and cancer, we have performed screens to identify protein interaction partners and genes regulated by the two JMJD2 proteins, JMJD2A and GASC1/JMJD2C. Specific antibodies have been used to identify promoter regions directly bound by JMJD2 proteins in a genome-wide location analysis. Complementary to this, changes in gene expression profiles caused by down-regulation of the JMJD2 proteins have been monitored. Target genes were identified in the esophageal carcinoma cell line, Kyse150, which has the GASC1 gene amplified. Interestingly, our data suggests that the JMJD2 proteins regulate a substantial number of genes involved in cell proliferation and mitosis, and consistent with this down-regulation of GASC1 appears to affect genomic stability. Results of this analysis together with the characterization of JMJD2 binding partners will be presented at the meeting.
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Document Type: Abstract

Publication date: May 1, 2008

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