Journal article
Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells
Amino acids, Vol.42(2-3), pp.887-898
02/01/2012
DOI: 10.1007/s00726-011-1004-1
PMCID: PMC3240695
PMID: 21805138
Abstract
Aberrant epigenetic repression of gene expression has been implicated in most cancers, including breast cancer. The nuclear amine oxidase, lysine-specific demethylase 1 (LSD1) has the ability to broadly repress gene expression by removing the activating mono- and di-methylation marks at the lysine 4 residue of histone 3 (H3K4me1 and me2). Additionally, LSD1 is highly expressed in estrogen receptor alpha negative (ER-) breast cancer cells. Since epigenetic marks are reversible, they make attractive therapeutic targets. Here we examine the effects of polyamine analog inhibitors of LSD1 on gene expression, with the goal of targeting LSD1 as a therapeutic modality in the treatment of breast cancer. Exposure of the ER-negative human breast cancer cells, MDA-MB-231 to the LSD1 inhibitors, 2d or PG11144, significantly increases global H3K4me1 and H3K4me2, and alters gene expression. Array analysis indicated that 98 (75 up and 23 down) and 477 (237 up and 240 down) genes changed expression by at least 1.5-fold or greater after treatment with 2d and PG11144, respectively. The expression of 12 up-regulated genes by 2d and 14 up-regulated genes by PG11144 was validated by quantitative RT-PCR. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that up-regulated gene expression by polyamine analogs is associated with increase of the active histone marks H3K4me1, H3K4me2 and H3K9act, and decrease of the repressive histone marks H3K9me2 and H3K27me3, in the promoter regions of the relevant target genes. These data indicate that the pharmacologic inhibition of LSD1 can effectively alter gene expression and that this therapeutic strategy has potential.
Details
- Title: Subtitle
- Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells
- Creators
- Qingsong Zhu - Johns Hopkins UniversityYi Huang - UPMC Hillman Cancer CenterLaurence J. Marton - University of California, San FranciscoPatrick M. Woster - Medical University of South CarolinaNancy E. Davidson - UPMC Hillman Cancer CenterRobert A. Casero - Johns Hopkins University
- Resource Type
- Journal article
- Publication Details
- Amino acids, Vol.42(2-3), pp.887-898
- DOI
- 10.1007/s00726-011-1004-1
- PMID
- 21805138
- PMCID
- PMC3240695
- NLM abbreviation
- Amino Acids
- ISSN
- 0939-4451
- eISSN
- 1438-2199
- Publisher
- Springer Nature
- Number of pages
- 12
- Grant note
- CA51085; CA98454; CA149095 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA KG088923 / Susan G. Komen for the Cure; Susan G. Komen Breast Cancer Foundation Samuel Waxman Cancer Research Foundation R01CA149095 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 02/01/2012
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383899202771
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