Abstract 4884: Polyamine analogues in combination with DFMO inhibits lysine-specific demethylase 1 and induces re-expression of aberrantly silenced genes

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Epigenetic gene silencing is an important mechanism for the loss of gene expression in cancer. Abnormal DNA CpG island hypermethylation and altered patterns of histone modifications are involved in aberrant silencing of tumor suppressor gene. The flavin-dependent lysine-specific demethylase 1 (LSD1) is the first enzyme identified to specifically demethylate Lysine 4 of histone H3. Methylation of H3K4 is an important mark associated with active chromatin transcription. The FAD-binding amine oxidase domain of LSD1 has considerable sequence homology to two polyamine oxidases SMO (spermine oxidase) and APAO (acetylpolyamine oxidase). Our laboratory has identified long chain polyamine analogues, named oligoamines, act as inhibitors of LSD1. Here we report the synergistic effects of specific oligoamines in combination treatment with 2-difluoromethylornithine (DFMO) in human colorectal cancer cells. DFMO is an inhibitor of ornithine decarboxylase (ODC), which is a rate-limiting enzyme to generate putrescine. Reducing the level of putrescine leads to accumulation of decarboxylated S-adenosylmethionine (dcSAM) and could subsequently result in alteration of DNA methyltransferase activity and changes in DNA methylation. In addition, DFMO treatment is known to increases uptake of circulating polyamines. Exposure of colorectal tumor cells to oligoamines and DFMO results in a synergistic global increase of H3K4me2 and induction of re-expression of aberrantly silenced genes including the secreted frizzled-related protein 2 (SFRP2) gene, which encodes Wnt signaling pathway antagonist and plays an anti-tumorigenesis role in colorectal cancer. Chromatin immunoprecipitation analysis indicates that the re-expression of SFRP2 is associated with increased H3K4me2 active marks at the gene promoter. The combination of LSD1-inhibiting oligoamines and DFMO represents a highly valuable and novel approach to epigenetic therapy of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4884.