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- W2810873923 abstract "Introduction The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in cell self-renewal, reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumour types. We have identified WDR5 as an epigenetic target in in vivo and in vitro shRNA screenings performed in MCF10DCIS.com (from now MCF10DCIS) breast cancer (BC) cells. Here, we show that WDR5 can regulate metastasis dissemination in BC by stimulating TGFB-induced EMT. Material and methods MCF10DCIS and MDAMB231 cells and six metastatic PDXs were used for in vivo and in vitro studies. Cells were transduced to silence WDR5 (shWDR5) or a neutral control (shLuc). Transcriptomic profiles were evaluated by RNA-seq in shLuc and shWDR5 PDXs and MCF10DCIS cells. Differentially expressed genes (DEGs) were identified using Log2FC>|0.6| and FDR t test for in vivo and in vitro experiments. Results and discussions WDR5 interference significantly inhibited tumour growth and in vitro migration of PDXs and MCF10DCIS cells and reduced metastatic burden of MDAMB231 cells in vivo . These data suggested that WDR5 may be involved in cell motility, promoting invasiveness and metastasis. Gene Ontology performed on DEGs highlighted an enrichment of functions related to EMT and TGFB signalling. Indeed, protein and mRNA levels of a series of gene implicated in EMT (e.g. SNAI1, TWIST1, CDH2, SNAI2, ZEB1) were strongly reduced in shWDR5 PDXs and MCF10DCIS cells, thus suggesting a regulatory role of WDR5 in EMT. H3K4me3 levels were globally affected and concordantly reduced at TSS level of SNAI1 and TWIST1 genes in shWDR5 MCF10DCIS cells, confirming that WDR5 can transcriptionally regulate EMT in BC. Moreover, the induction of EMT by TGFB treatment can be abrogated in WDR5-deficient cells, suggesting that the EMT induced by TGFB is WDR5-dependent. Conclusion Our evidences support a model in which WDR5 is responsible for mediating the epithelial-to-mesenchymal transition and metastasis dissemination in BC. WDR5 is essential for TGFB response and its inhibition may be a successful approach to prevent progression of metastatic BC." @default.
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- W2810873923 date "2018-06-01" @default.
- W2810873923 modified "2023-09-25" @default.
- W2810873923 title "PO-178 WDR5 promotes metastasis dissemination in breast cancer" @default.
- W2810873923 doi "https://doi.org/10.1136/esmoopen-2018-eacr25.217" @default.
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