Abstract
PurposeThis study aims to identify downstream target genes regulated by lysine-specific demethylase 1 (LSD1) in colon cancer cells and investigate the molecular mechanisms of LSD1 influencing invasion and metastasis of colon cancer.MethodWe obtained the expression changes of downstream target genes regulated by small-interfering RNA-LSD1 and LSD1-overexpression via gene expression profiling in two human colon cancer cell lines. An Affymetrix Human Transcriptome Array 2.0 was used to identify differentially expressed genes (DEGs). We screened out LSD1-target gene associated with proliferation, metastasis, and invasion from DEGs via Gene Ontology and Pathway Studio. Subsequently, four key genes (CABYR, FOXF2, TLE4, and CDH1) were computationally predicted as metastasis-related LSD1-target genes. ChIp-PCR was applied after RT-PCR and Western blot validations to detect the occupancy of LSD1-target gene promoter-bound LSD1.ResultA total of 3633 DEGs were significantly upregulated, and 4642 DEGs were downregulated in LSD1-silenced SW620 cells. A total of 4047 DEGs and 4240 DEGs were upregulated and downregulated in LSD1-overexpressed HT-29 cells, respectively. RT-PCR and Western blot validated the microarray analysis results. ChIP assay results demonstrated that LSD1 might be negative regulators for target genes CABYR and CDH1. The expression level of LSD1 is negatively correlated with mono- and dimethylation of histone H3 lysine4(H3K4) at LSD1- target gene promoter region. No significant mono-methylation and dimethylation of H3 lysine9 methylation was detected at the promoter region of CABYR and CDH1.ConclusionLSD1- depletion contributed to the upregulation of CABYR and CDH1 through enhancing the dimethylation of H3K4 at the LSD1-target genes promoter. LSD1- overexpression mediated the downregulation of CABYR and CDH1expression through decreasing the mono- and dimethylation of H3K4 at LSD1-target gene promoter in colon cancer cells. CABYR and CDH1 might be potential LSD1-target genes in colon carcinogenesis.
Highlights
Colon cancer is known as the third most common malignancy throughout the world [1]
lysine-specific demethylase 1 (LSD1)- depletion contributed to the upregulation of CABYR and CDH1 through enhancing the dimethylation of H3K4 at the LSD1-target genes promoter
LSD1- overexpression mediated the downregulation of CABYR and CDH1expression through decreasing the mono- and dimethylation of H3K4 at LSD1-target gene promoter in colon cancer cells
Summary
Recurrence and metastasis are the primary causes of death among colon cancer patients. Growing evidence has indicated that lysine-specific demethylase 1 is associated with tumorigenesis and growth, invasive ability, metastasis, and therapeutic resistance [2,3,4,5]. A broad scope of genetic and epigenetic modifications plays an important role in www.impactjournals.com/oncotarget the development and tumorigenesis of colon cancers. Used as a molecular “hook” that affects with LSD1- CoREST complex mutually, the Snail/Gfi-1 domain of Snail/Slug ensembles a histone H3-like structure; this complex is conveyed to its targeted gene promoters through the binding of E-box and zinc-finger motifs [7,8,9]. The LSD1CoREST complex works as a reversible nanoscale binding clamp and recruits and anchors various substrate peptides with high sequence similarity to H3-histone tail [10,11,12,13]
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