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Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis [ChIP-Seq]

ABSTRACT: Here we found that Cbx8 knockdown in MMTV-Myc and MDA-MB-231-Luc cells reduces H3K4me3 mark on Notch-network genes

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE71003 | GEO | 2016/06/21

SECONDARY ACCESSION(S): PRJNA290085

REPOSITORIES: GEO

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Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis [RNA-Seq]

Project description:Here we show that in MMTV-Myc cells (1) MS culture enriches for aggressive breast cancer cells compared to the bulk cells, (2) Cbx8 knockdown reduces Notch-network gene expression.

2016-06-21 | GSE71076 | GEO

Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis.

Project description:Chromatin-mediated processes influence the development and progression of breast cancer. Using murine mammary carcinoma-derived tumorspheres as a functional readout for an aggressive breast cancer phenotype, we performed a loss-of-function screen targeting 60 epigenetic regulators. We identified the Polycomb protein Cbx8 as a key regulator of mammary carcinoma both in vitro and in vivo. Accordingly, Cbx8 is overexpressed in human breast cancer and correlates with poor survival. Our genomic analyses revealed that Cbx8 positively regulates Notch signaling by maintaining H3K4me3 levels on Notch-network gene promoters. Ectopic expression of Notch1 partially rescues tumorsphere formation in Cbx8-depleted cells. We find that Cbx8 associates with non-PRC1 complexes containing the H3K4 methyltransferase complex component WDR5, which together regulate Notch gene expression. Thus, our study implicates a key non-canonical role for Cbx8 in promoting breast tumorigenesis.

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Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis

Project description:Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis

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Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-06-21 | GSE71077 | GEO

Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis [ChIP-Seq]

Project description:Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis [ChIP-Seq]

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Expression data from human breast cancer cells MDA-MB-231-Luc knockdown for RRAS2 expression.

Project description:We used microarrays to investigate gene expression changes induced by the inhibition of RRAS2 expression using shRNA techniques to stably knockdown the endogenous transcripts of this GTPase in human MDA-MB-231-Luc cells. MDA-MB-231-Luc shControl (MDA-Control) and RRAS2-deficient (KDRRAS2.p1) in exponential growth phase were selected for RNA extraction and and hybridization on Affymetrix microarrays.

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CBX8 KO and WT re-expression RNA-seq

Project description:T98G CBX8 KO and WT re-expression RNA-seq analysis to identify potential CBX8 gene targets

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Expression data from human breast cancer cells MDA-MB-231-Luc knockdown for RRAS2 expression.

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REPROGRAMMING CBX8-PRC1 FUNCTION WITH A POSITIVE ALLOSTERIC MODULATOR

Project description:Canonical targeting of Polycomb Repressive Complex 1 (PRC1) to repress developmental genes is mediated by cell type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7 and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.

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CBX8 promotes LUAD growth and metastasis through transcriptional repression of CDKN2C and SCEL

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