Inhibition of histone demethylase, LSD2 (KDM1B), attenuates DNA methylation and increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells

Tiffany A. Katz, Shauna N. Vasilatos, Emily Harrington, Steffi Oesterreich, Nancy E. Davidson, Yi Huang

Research output: Contribution to journalArticlepeer-review

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, RARβ, ERα, 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.

Original languageEnglish (US)
Pages (from-to)99-108
Number of pages10
JournalBreast Cancer Research and Treatment
Volume146
Issue number1
DOIs
StatePublished - Jul 2014

Keywords

  • Apoptosis
  • Breast cancer
  • Combination therapy
  • DNA methylation
  • DNMT inhibitor
  • LSD2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Inhibition of histone demethylase, LSD2 (KDM1B), attenuates DNA methylation and increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells'. Together they form a unique fingerprint.

Cite this