Journal article
Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes
Proceedings of the National Academy of Sciences - PNAS, Vol.104(19), pp.8023-8028
05/08/2007
DOI: 10.1073/pnas.0700720104
PMCID: PMC1857229
PMID: 17463086
Abstract
Epigenetic chromatin modification is a major regulator of eukaryotic gene expression, and aberrant epigenetic silencing of gene expression contributes to tumorigenesis. Histone modifications include acetylation, phosphorylation, and methylation, resulting in a combination of histone marks known collectively as the histone code. The chromatin marks at a given promoter determine, in part, whether specific promoters are in an open/active conformation or closed/repressed conformation. Dimethyl-lysine 4 histone H3 (H3K4me2) is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by the lysine-specific demethylase 1 (LSD1), a homologue of polyamine oxidases, may broadly repress gene expression. We now report that novel biguanide and bisguanidine polyamine analogues are potent inhibitors of LSD1. These analogues inhibit LSD1 in human colon carcinoma cells and affect a reexpression of multiple, aberrantly silenced genes important in the development of colon cancer, including members of the secreted frizzle-related proteins (
SFRPs
) and the
GATA
family of transcription factors. Furthermore, we demonstrate by chromatin immunoprecipitation analysis that the reexpression is concurrent with increased H3K4me2 and acetyl-H3K9 marks, decreased H3K9me1 and H3K9me2 repressive marks. We thus define important new agents for reversing aberrant repression of gene transcription.
Details
- Title: Subtitle
- Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes
- Creators
- Yi Huang - Johns Hopkins University School of MedicineEriko Greene - Johns Hopkins UniversityTracy Murray StewartAndrew C. GoodwinStephen B. BaylinPatrick M. Woster - Wayne State UniversityRobert A. Casero
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.104(19), pp.8023-8028
- Publisher
- National Academy of Sciences
- DOI
- 10.1073/pnas.0700720104
- PMID
- 17463086
- PMCID
- PMC1857229
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Language
- English
- Date published
- 05/08/2007
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383900802771
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