Abstract
Abstract Silencing of genes by DNA hypermethylation contributes to cancer progression and has been shown to occur with increased frequency at specific genomic loci. However, the precise mechanisms underlying the establishment and maintenance of aberrant methylation marks are still elusive. The de novo DNA methyltransferase 3B (DNMT3B) has been suggested to play an important role in the generation of cancer-specific methylation patterns. Previous studies have shown that a reduction of DNMT3B protein levels induces antiproliferative effects in cancer cells that were attributed to the demethylation and reactivation of tumor suppressor genes. However, methylation changes after depletion of DNMT3B protein have not been analyzed in detail yet. We performed short- and long-term RNAi knockdown experiments to reduce DNMT3B protein levels in colon cancer cell lines and analyzed genome-wide DNA methylation changes on HumanMethylation27 and HumanMethylation450 Illumina bead chips. Our results confirm that depletion of DNMT3B specifically reduced the proliferation rate of DNMT3B-overexpressing colon cancer cell lines. All colon cancer cell lines tested contain a mutant K-Ras and we conclude that K-Ras status - in contrast to DNMT3B protein overexpression levels - does not impact on anti-proliferative responses after DNMT3B knockdown. However, in contrast to the dramatic alterations of DNA methylation observed in DNMT1; DNMT3B double knockout cells (DKO), genome-scale DNA methylation profiling failed to reveal methylation changes at putative DNMT3B target genes, even in the complete absence of DNMT3B. These results show that DNMT3B is dispensable for the maintenance of aberrant DNA methylation patterns in human colon cancer cells and they have important implications for the development of targeted DNA methyltransferase inhibitors as epigenetic cancer drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1036. doi:1538-7445.AM2012-1036
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