PMID- 24924415
OWN - NLM
STAT- MEDLINE
DCOM- 20150818
LR  - 20231213
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Linking)
VI  - 146
IP  - 1
DP  - 2014 Jul
TI  - Inhibition of histone demethylase, LSD2 (KDM1B), attenuates DNA methylation and 
      increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells.
PG  - 99-108
LID - 10.1007/s10549-014-3012-9 [doi]
AB  - 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, RARbeta, ERalpha, 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.
FAU - Katz, Tiffany A
AU  - Katz TA
AD  - UPMC Cancer Research Pavilion, University of Pittsburgh Cancer Institute, Suite 
      500, 5150 Centre Ave, Pittsburgh, PA, 15232, USA.
FAU - Vasilatos, Shauna N
AU  - Vasilatos SN
FAU - Harrington, Emily
AU  - Harrington E
FAU - Oesterreich, Steffi
AU  - Oesterreich S
FAU - Davidson, Nancy E
AU  - Davidson NE
FAU - Huang, Yi
AU  - Huang Y
LA  - eng
GR  - P30CA047904/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140613
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Histones)
RN  - 0 (RNA, Small Interfering)
RN  - EC 1.14.11.- (Histone Demethylases)
RN  - EC 1.14.11.- (KDM1B protein, human)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis/*drug effects/*genetics
MH  - Breast Neoplasms/*genetics/*metabolism
MH  - Cell Line, Tumor
MH  - DNA (Cytosine-5-)-Methyltransferases/*antagonists & inhibitors
MH  - *DNA Methylation
MH  - *Drug Resistance, Neoplasm
MH  - Female
MH  - Gene Silencing
MH  - Histone Demethylases/*genetics
MH  - Histones/metabolism
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Methylation
MH  - RNA, Small Interfering/genetics
MH  - Transcriptional Activation/drug effects
MH  - Tumor Stem Cell Assay
EDAT- 2014/06/14 06:00
MHDA- 2015/08/19 06:00
CRDT- 2014/06/14 06:00
PHST- 2014/05/23 00:00 [received]
PHST- 2014/05/26 00:00 [accepted]
PHST- 2014/06/14 06:00 [entrez]
PHST- 2014/06/14 06:00 [pubmed]
PHST- 2015/08/19 06:00 [medline]
AID - 10.1007/s10549-014-3012-9 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2014 Jul;146(1):99-108. doi: 10.1007/s10549-014-3012-9. 
      Epub 2014 Jun 13.