Journal article
Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells
Carcinogenesis (New York), Vol.34(6), pp.1196-1207
06/01/2013
DOI: 10.1093/carcin/bgt033
PMCID: PMC3670252
PMID: 23354309
Abstract
Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However, the underlying mechanisms are largely unknown. In this study, we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels of HDAC isozymes in triple-negative breast cancer (TNBC) cells. Small interfering RNA (siRNA)-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, pargyline, and HDAC inhibitor, SAHA (Vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA-induced reexpression of a subset of aberrantly silenced genes, such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1-deficient MDA-MB-231 cells. Furthermore, cotreatment with RGS16 siRNA reversed the downregulation of nuclear factor-kappaB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor.
Details
- Title: Subtitle
- Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells
- Creators
- Shauna N. Vasilatos - UPMC Hillman Cancer CenterTiffany A. Katz - University of PittsburghSteffi Oesterreich - University of PittsburghYong Wan - University of PittsburghNancy E. Davidson - UPMC Hillman Cancer CenterYi Huang - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Carcinogenesis (New York), Vol.34(6), pp.1196-1207
- Publisher
- Oxford University Press
- DOI
- 10.1093/carcin/bgt033
- PMID
- 23354309
- PMCID
- PMC3670252
- ISSN
- 0143-3334
- eISSN
- 1460-2180
- Language
- English
- Date published
- 06/01/2013
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383279902771
Metrics
18 Record Views