Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis

• RNAi screen in sphere culture identifies Cbx8 in promoting breast cancer
• Cbx8 is upregulated in human breast cancer and correlates with poor survival
• Cbx8 promotes mammary tumors in vivo via Notch pathway activation
• Cbx8 cooperates with Wdr5 to sustain Notch expression by regulating H3K4me3

SummaryChromatin-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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