Histone methylation is a complicate and dynamic epigenetic modification that regulates gene transcription, chromosomal structure and cell differentiation. Here, we discovered the interaction between the H3K4 demethylase, lysine specific demethylase 1 (LSD1, an important component of CoREST repressor complex) and the H3K27 methyltransferase, enhancer of zeste homolog 2 (EZH2, an essential component of PRC2). Immuno-precipitation and GST-pull down assay were performed to observe the interaction between the proteins. The MCF-7 cells were cultured and transfected with the siRNA. The mRNA and proteins were examined by using the real-time polymerase chain reaction (RT-PCR) and western blot assay, respectively. HPLC and LC–MS/MS analysis were performed to purify the proteins. RT-PCR-based quantitative ChIP analysis were performed. LSD1 interacts with histone modification protein EZH2 in MCF-7 cells. LSD1 and EZH2 target a few common genes. LSD1 knockdown and EZH2 knockdown affect protein expression. LSD1 knockdown and EZH2 knockdown affect the proteins involving in IFN signaling pathway. LSD1 and EZH2 modify histone methylation at IRF9 gene locus. We systematically analyzed the proteins that are affected by either LSD1 or EZH2 knockdown with proteomic approaches and identified that the interferon pathway and some other pathways are commonly affected. The interaction between LSD1 and EZH2 stabilizes the binding of LSD1 to the promoter region of IRF9, which is a key transcription factor of the interferon pathway. In conclusion, our study revealed that the coordination between histone demethylases and methyl-transferases might serve as a double lock system to suppress the expression of interferon stimulated genes.