Journal article
Inhibition of histone demethylase, LSD2 (KDM1B), attenuates DNA methylation and increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells
Breast cancer research and treatment, Vol.146(1), pp.99-108
07/01/2014
DOI: 10.1007/s10549-014-3012-9
PMID: 24924415
Abstract
Increasing evidence suggests that dysfunction of histone lysine demethylase is associated with abnormal chromatin remodeling and gene silencing, contributing to breast tumorigenesis. In silico analysis shows that the newly identified histone demethylase lysine-specific demethylase 2 is highly expressed in breast cancer, especially in invasive tumors. However, it is currently unknown how LSD2 regulates chromatin remodeling and gene expression regulation in breast cancer. Using short hairpin RNA, we stably knocked down LSD2 (LSD2-KD) in MDA-MB-231 breast cancer cells. LSD2-KD led to accumulation of H3K4me1/2 without changing methylation levels of other key histone lysine residues, suggesting that LSD2 acts as a bona fide H3K4 demethylase in breast cancer cells. LSD2-KD resulted in decreased colony formation and attenuated global DNA methylation in MDA-MB-231 cells. Additionally, treatment with the DNMT inhibitor, 5-aza-deoxycytidine (DAC), synergistically increased mRNA expression of aberrantly silenced genes important in breast cancer development, including PR, RAR beta, ER alpha, SFRP1, SFRP2, and E-cadherin in LSD2-KD cells. Furthermore, LSD2-KD cells are more susceptible to cell death than scramble controls, and combined treatment with tranylcypromine, an LSD2 inhibitor, and DAC resulted in synergistic growth inhibition of breast cancer cells. DNMT inhibition by DAC in LSD2-KD cells led to internucleosomal DNA fragmentation, enhanced PARP cleavage and increased sub-G1 apoptotic cell population. These results demonstrate an important role for LSD2 in regulation of DNA methylation and gene silencing in breast cancer, and suggest that inhibition of LSD2 in combination with DNA methyltransferase inhibition represents a novel approach for epigenetic therapy of breast cancer.
Details
- Title: Subtitle
- Inhibition of histone demethylase, LSD2 (KDM1B), attenuates DNA methylation and increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells
- Creators
- Tiffany A. Katz - UPMC Hillman Cancer CenterShauna N. Vasilatos - UPMC Hillman Cancer CenterEmily Harrington - UPMC Hillman Cancer CenterSteffi Oesterreich - UPMC Hillman Cancer CenterNancy E. Davidson - UPMC Hillman Cancer CenterYi Huang - UPMC Hillman Cancer Center
- Resource Type
- Journal article
- Publication Details
- Breast cancer research and treatment, Vol.146(1), pp.99-108
- Publisher
- Springer Nature
- DOI
- 10.1007/s10549-014-3012-9
- PMID
- 24924415
- ISSN
- 0167-6806
- eISSN
- 1573-7217
- Number of pages
- 10
- Grant note
- P30CA047904 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Samuel Winters Foundation Breast Cancer Research Foundation Competitive Medical Research Fund of UPMC
- Language
- English
- Date published
- 07/01/2014
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383282502771
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