Abnormal activities of
histone lysine demethylases (KDMs) and
lysine deacetylases (HDACs) are associated with aberrant gene expression in
breast cancer development. However, the precise molecular mechanisms underlying the crosstalk between KDMs and HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment of human
breast cancer cells with inhibitors targeting the
zinc cofactor dependent class I/II HDAC, but not
NAD(+) dependent class III HDAC, led to significant increase of H3K4me2 which is a specific substrate of
histone lysine-specific demethylase 1 (LSD1) and a key
chromatin mark promoting transcriptional activation. We also demonstrated that inhibition of LSD1 activity by a pharmacological inhibitor,
pargyline, or
siRNA resulted in increased acetylation of H3K9 (AcH3K9). However,
siRNA knockdown of LSD2, a homolog of LSD1, failed to alter the level of AcH3K9, suggesting that LSD2 activity may not be functionally connected with HDAC activity. Combined treatment with LSD1 and
HDAC inhibitors resulted in enhanced levels of H3K4me2 and AcH3K9, and exhibited synergistic growth inhibition of
breast cancer cells. Finally, microarray screening identified a unique subset of genes whose expression was significantly changed by combination treatment with inhibitors of LSD1 and HDAC. Our study suggests that LSD1 intimately interacts with
histone deacetylases in human
breast cancer cells. Inhibition of
histone demethylation and deacetylation exhibits cooperation and synergy in regulating gene expression and growth inhibition, and may represent a promising and novel approach for epigenetic
therapy of
breast cancer.