Journal article
Novel Oligoamine Analogues Inhibit Lysine-Specific Demethylase 1 and Induce Reexpression of Epigenetically Silenced Genes
Clinical cancer research, Vol.15(23), pp.7217-7228
12/01/2009
DOI: 10.1158/1078-0432.CCR-09-1293
PMCID: PMC2927136
PMID: 19934284
Abstract
Purpose: Abnormal DNA CpG island hypermethylation and transcriptionally repressive histone modifications are associated with the aberrant silencing of tumor suppressor genes. Lysine methylation is a dynamic, enzymatically controlled process. Lysine-specific demethylase 1 (LSD1) has recently been identified as a histone lysine demethylase. LSD1 specifically catalyzes demethylation of mono- and dimethyl-lysine 4 of histone 3 (H3K4), key positive chromatin marks associated with transcriptional activation. We hypothesized that a novel class of oligoamine analogues would effectively inhibit LSD1 and thus cause the reexpression of aberrantly silenced genes.
Experimental Design: Human colorectal cancer cells were treated with the oligoamines and changes in mono- and dimethyl-H3K4 and other chromatin marks were monitored. In addition, treated cells were evaluated for the reexpression of the aberrantly silenced secreted frizzled-related proteins (SFRP) Wnt signaling pathway antagonist genes. Finally, the effects of the LSD1 inhibitors were evaluated in an in vivo xenograft model.
Results: Treatment of HCT116 human colon adenocarcinoma cells in vitro resulted in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpresSion is also accompanied by a decrease in H3K9me2 repressive mark. Importantly, cotreatment with low doses of oligoamines and a DNA methyltransferase inhibitor highly induces the reexpression of the aberrantly silenced SFRP2 gene and results in significant inhibition of the growth of established tumors in a human colon tumor model in vivo.
Conclusions: The use of LSD1-inhibiting oligoamine analogues in combination with DNA methyltransferase inhibitors represents a highly promising and novel approach for epigenetic therapy of cancer. (Clin Cancer Res 2009;15(23):7217-28)
Details
- Title: Subtitle
- Novel Oligoamine Analogues Inhibit Lysine-Specific Demethylase 1 and Induce Reexpression of Epigenetically Silenced Genes
- Creators
- Yi Huang - Sidney Kimmel Comprehensive Cancer CenterTracey Murray Stewart - Johns Hopkins UniversityYu Wu - Johns Hopkins UniversityStephen B. Baylin - Johns Hopkins UniversityLaurence J. Marton - Progen PharmaceuticalsBrandy Perkins - Johns Hopkins UniversityRichard J. Jones - Johns Hopkins UniversityPatrick M. Woster - Wayne State UniversityRobert A. Casero - Johns Hopkins University
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.15(23), pp.7217-7228
- DOI
- 10.1158/1078-0432.CCR-09-1293
- PMID
- 19934284
- PMCID
- PMC2927136
- NLM abbreviation
- Clin Cancer Res
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 12
- Grant note
- CA 51085; CA 98454 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01CA043318 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Samuel Waxman Cancer Research Foundation KG 088923 / Cure Foundation
- Language
- English
- Date published
- 12/01/2009
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383909702771
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