DNA and Histone Methylation as Cancer Targets by Atsushi Kaneda & Yu-ichi Tsukada

Author:Atsushi Kaneda & Yu-ichi Tsukada
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

DIRAS3 is silenced in most ovarian and breast cancer cell lines [246] and can inhibit growth of breast and ovarian cancer cell lines when the expression constructs are introduced in the cancer cells. This growth inhibition is accomplished by downregulation of cyclin D1 and up-regulation of p21WAF1/CIP1. In a study of ovarian cancer, cancer cell lines showed DIRAS3 silencing and CGI I hypermethylation with frequencies of 80% (8/10) and 60% (6/10), respectively [54]. Analysis of cancer tissues showed 88% (35/40) of the cancers expressed lower levels of DIRAS3 than normal ovarian tissues. CGI I and CGI II were hypermethylated in 31% (13/42) and 12% (5/42) of cancers, respectively. All cancers with hypermethylation showed reduced expression of the gene. Frequent LOH (41%, 9/22) occurred in these cancers, which led to loss of the active paternal allele. In spite of the frequent LOH, there were many cancers that retained heterozygosity and thus the gene was also silenced by aberrant hypermethylation at the CGIs.

CGI methylation status of the DIRAS3 gene has also been reported in breast cancer cell lines, in which DIRAS3 was silenced. CGIs I and III were frequently hypermethylated and CGI II showed either hypermethylation or hypomethylation in the cell lines [248]. Aberrant methylation at the DIRAS3-CGIs was also observed in breast cancer tissues [53, 248]. However, no characteristic feature was seen in the aberrant methylation, such as hypermethylation or hypomethylation, and frequencies at each of the CGIs. Because DIRAS3 expression and chromosomal abnormality were not analyzed in either of these studies on breast cancer tissues, it is not clear whether the observed aberrant methylation alters DIRAS3 expression and whether aberrant methylation is due to changes in DNA methylation or loss of methylated or unmethylated alleles. On the other hand, some studies suggest that histone modifications are also involved in inactivation of the DIRAS3 gene. A histone deacetylase inhibitor, trichostatin A, could reactivate gene expression in breast cancer cells, in which DIRAS3 is repressed without hypermethylation at CGI II [59]. Breast cancer tissues highly express JMJD2A, a histone demethylase, which acts on tri- and di-methylated H3K9 and H3K36. Expression of this enzyme is positively correlated with progression of cancers and negatively correlated with DIRAS3 expression. JMJD2A binds the DIRAS3 promoter together with HDAC1 and HDAC3 and represses gene expression [122].

Many other types of cancer, such as follicular thyroid carcinoma, oligodendroglioma, and HCC, have downregulated DIRAS3 and shown aberrant methylation of DIRAS3 CGIs. LOH of the DIRAS3 locus was found in 64% (9/14) of follicular thyroid carcinoma [233] and 53% (20/38) of oligodendrogliomas [190]. A LOH case of follicular thyroid carcinoma showed hypermethylation at all DIRAS3 CGIs and most LOH cases of oligodendroglioma showed hypermethylation of at least one of three CGIs. These indicate deletion of the paternal allele. Furthermore, among oligodendroglioma cases with ROH, several cases showed hypermethylation of the CGIs, resulting in reduced expression of the gene. In contrast to the above two types of tumors, LOH of the DIRAS3 locus was a very rare event in HCC, which showed frequent reduction of DIRAS3 expression [80].

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