Upregulation of CD11b and CD86 through LSD1 inhibition promotes myeloid differentiation and suppresses cell proliferation in human monocytic leukemia cells

LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 i...

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Published in:Oncotarget 2017-10, Vol.8 (49), p.85085-85101
Main Authors: Fang, Jianwu, Ying, Haiyan, Mao, Ting, Fang, Yanjia, Lu, Yuan, Wang, He, Zang, Irene, Wang, Zhaofu, Lin, Ying, Zhao, Mengxi, Luo, Xiao, Wang, Zongyao, Zhang, Yan, Zhang, Chao, Xiao, Wei, Wang, Yan, Tan, Wei, Chen, Zhui, Lu, Chris, Atadja, Peter, Li, En, Zhao, Kehao, Liu, Jianfeng, Gu, Justin
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Language:English
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Summary:LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells. Cell surface expression of CD11b and CD86 is significantly and dynamically increased in human AML cells upon sustained LSD1 inhibition. Chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) analyses of histone marks revealed that there is a specific increase of H3K4me2 modification and an accompanied increase of H3K4me3 modification at the respective CD11b and CD86 promoter region, whereas the global H3K4me2 level remains constant. Consistently, inhibition of LSD1 significantly blocks tumor growth and induces a prominent increase of CD11b and CD86. Taken together, our results demonstrate the anti-tumor properties of LSD1 inhibition on human AML cell line and mouse xenograft model. Our findings provide mechanistic insights into the LSD1 functions in controlling both differentiation and proliferation in AML.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.18564