title: Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes.
abstract: Epigenetic gene silencing is an important mechanism in the initiation and progression of cancer. Abnormal DNA CpG island hypermethylation and histone modifications are involved in aberrant silencing of tumour-suppressor genes. LSD1 (lysine-specific demethylase 1) was the first enzyme identified to specifically demethylate H3K4 (Lys(4) of histone H3). Methylated H3K4 is an important mark associated with transcriptional activation. The flavin adenine dinucleotide-binding amine oxidase domain of LSD1 is homologous with two polyamine oxidases, SMO (spermine oxidase) and APAO (N(1)-acetylpolyamine oxidase). We have demonstrated previously that long-chain polyamine analogues, the oligoamines, are inhibitors of LSD1. In the present paper we report the synergistic effects of specific oligoamines in combination with DFMO (2-difluoromethylornithine), an inhibitor of ornithine decarboxylase, in human colorectal cancer cells. DFMO treatment depletes natural polyamines and increases the uptake of exogenous polyamines. The combination of oligoamines and DFMO results in a synergistic re-expression of aberrantly silenced tumour-suppressor genes, including SFRP2 (secreted frizzled-related protein 2), which encodes a Wnt signalling pathway antagonist and plays an anti-tumorigenic role in colorectal cancer. The treatment-induced re-expression of SFRP2 is associated with increased H3K4me2 (di-methyl H3K4) in the gene promoter. The combination of LSD1-inhibiting oligoamines and DFMO represents a novel approach to epigenetic therapy of cancer.
authors: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: Yu
authors: Y
authors: Wu
authors: Nora
authors: N
authors: Steinbergs
authors: Tracy
authors: T
authors: Murray-Stewart
authors: Laurence J
authors: LJ
authors: Marton
authors: Robert A
authors: RA
authors: Casero
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D000518:Eflornithine / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D016153:Genes, Suppressor; D045325:HCT116 Cells; D019073:HT29 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology; D011401:Promoter Regions, Genetic
chemical_list: D011073:Polyamines; D056466:Histone Demethylases; D000518:Eflornithine