Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis

Chi Yeh Chung, Zhen Sun, Gavriel Mullokandov, Almudena Bosch, Zulekha A. Qadeer, Esma Cihan, Zachary Rapp, Ramon Parsons, Julio A. Aguirre-Ghiso, Eduardo F. Farias, Brian D. Brown, Alexandre Gaspar-Maia, Emily Bernstein

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)472-486
Number of pages15
JournalCell reports
Volume16
Issue number2
DOIs
StatePublished - Jul 12 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Chung, C. Y., Sun, Z., Mullokandov, G., Bosch, A., Qadeer, Z. A., Cihan, E., Rapp, Z., Parsons, R., Aguirre-Ghiso, J. A., Farias, E. F., Brown, B. D., Gaspar-Maia, A., & Bernstein, E. (2016). Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis. Cell reports, 16(2), 472-486. https://doi.org/10.1016/j.celrep.2016.06.002