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AEBP2’s roles in cell migration and Polycomb Repressive Complex 2 (PRC2)

ABSTRACT: Aebp2 encodes a zinc finger protein that is associated with the Polycomb Repressive Complex 2 (PRC2). The alternative promoters and protein isoforms of Aebp2 have been characterized in this study. Aebp2 is controlled through three alternative promoters, deriving three different transcripts which encode the embryonic (32 kDa) and somatic (52 kDa) forms. Chromatin ImmunoPrecipitation (ChIP) experiments revealed that AEBP2 binds to its own promoter as well as the promoters of Jarid2 and Snai2. While the embryonic form acts as a transcriptional repressor for Snai2, the somatic form functions as a transcriptional activator for Jarid2, Aebp2 and Snai2. Cell migration assays suggest that the Aebp2 somatic form can enhance cell migration. This is consistent with the functional association of Aebp2 with migratory neural crest cells. Overall, the two protein isoforms of AEBP2 may have opposite functions for the PcG target genes, and may play significant roles in cell migration during development.

ORGANISM(S): Mus musculus

PROVIDER: GSE62680 | GEO | 2015/10/23

SECONDARY ACCESSION(S): PRJNA264785

REPOSITORIES: GEO

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Project description:We investigated how the biologically active form of vitamin D (1,25(OH)2D3) inhibits the epithelial-to-mesenchymal transition (EMT), a critical step in the development of a migratory phenotype in epithelial tumor cells, as well as migration in general, using osteosarcoma (OS) as a model. We looked at how 1,25(OH)2D3 affected pre- and post-EMT migratory states in non-metastatic MG63 and metastatic LM7 OS cell models. In scratch and Boyden chamber assays, 1,25(OH)2D3 inhibited cell migration and invasion, but LM7 cells responded significantly less than MG63 cells (50 vs 26 percent decrease, respectively). 1,25(OH)2D3 inhibited the expression of EMT-inducing genes (e.g., SNAI2) and extracellular contact regulatory genes in MG63 cells but not in LM7 cells (e.g., CD44, MMP3). In comparison to MG63 cells, LM7 cells had significantly lower baseline VDR transcript levels but higher SNAI2 transcript levels. Furthermore, ATAC-seq analysis revealed that 1,25(OH)2D3 epigenetically repressed SNAI2 in MG63 cells, implying that LM7 cells may be constitutively induced to undergo EMT via VDR de-repression mediated by increased SNAI2 levels. Both cell lines appeared to activate an antioxidative pathway involving SOD2 upregulation and concurrent reactive oxygen species (ROS) reduction (e.g., H2O2). ATAC-seq analysis revealed that 1,25(OH)2D3 does not epigenetically regulate SOD2 in MG63 cells, implying a previously unknown indirect link promoting anti-EMT and anti-metastatic oxidation states in both OS cell lines. We studied the fate and migration of mouse hair follicle stem cell progenitor cells after wounding with or without the Vdr because cutaneous wounding and metastasis involve similar signaling factors that regulate cell migration. Conditional loss of Vdr in epithelial progenitor cells promoted cell migration and wound healing in comparison to control animals, indicating that Vdr signaling inhibits cell migration in general. Our findings show that vitamin D signaling inhibits cell migration both in vivo and in vitro, and that inhibiting reactive oxygen species (ROS) in both pre-EMT and post-EMT OS cells is a possible vitamin D mechanism and therapeutic strategy for preventing the onset and progression of OS. MG63 human osteosarcoma cell line treated with vehicle (ethanol) or 1,25(OH)D (10nM) for 24 and 48 hours.

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AEBP2’s roles in cell migration and Polycomb Repressive Complex 2 (PRC2)

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