Abstract 4877: Polyamine analogues modulate gene expression by inhibiting KDM1/LSD1 and altering chromatin structure in human breast cancer cells

Abstract

Abstract Gene expression can be modulated through histone methylation, which is tightly control by the balance of histone methytransferase and demethylase. Methylation (mono-, di- and tri-methylation) of lysine 4 of histone 3 is associated with active gene transcription. Lysine-specific demethylase 1 (KDM1/LSD1) can enzymatically demethylate mono- and di-methyl H3K4 that leads to suppression of gene transcription. Our previous studies demonstrated that a novel class of polyamine analogues can effectively inhibit KDM1/LSD1 and induce re-expression of candidate epigenetically silenced genes. The purpose of this study was to examine the molecular effects of polyamine analogues, 2d and PG11144, on global gene expression profile by inhibition of KDM/LSD1 in estrogen receptor-negative MDA-MB-231 breast cancer cells. The possible mechanisms of polyamine analogues mediating modulation of gene expression were also investigated. Treatment with polyamine analogous, 2d or PG11144, significantly increases global histone 3 dimethylation at lysine 4 (H3K4me2), as well as altering gene expression. There are 274 and 625 genes changed at least 2-fold after treatment with 2d and PG11144 respectively. The genes’ expression levels of twelve 2d up-regulated and fourteen PG11144 up-regulated genes were confirmed by real-time RT-PCR. Chromatin immunoprecipitation analysis demonstrated that up-regulated gene expression by polyamine analogous is associated with up-regulated active histone marks (H3K4me, H3K4me2 and ActH3K9) and down-regulated repressive histone marks (H3K9me2 and H3K27me3) in the promoter regions of the relevant target genes. Supported by NIH CA 88843, CA51085, Breast Cancer Research Foundation, and Komen for the Cure KG080923. 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 4877.