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

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 16 Issue 2 Pg. 472-486 (07 12 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27346354 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Histones
• Intracellular Signaling Peptides and Proteins
• Mitochondrial Membrane Transport Proteins
• Polycomb-Group Proteins
• Proteins
• Receptors, Notch
• Wdr5 protein, mouse
• Cbx8 protein, mouse
• Polycomb Repressive Complex 1

Topics

• Animals
• Carcinogenesis (metabolism)
• Cell Line, Tumor
• Epigenesis, Genetic
• Epithelial Cells (metabolism)
• Female
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Genetic Loci
• Histones (metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins
• Mammary Neoplasms, Animal (genetics, metabolism, pathology)
• Mice, Transgenic
• Mitochondrial Membrane Transport Proteins (physiology)
• Neoplastic Stem Cells (metabolism)
• Polycomb Repressive Complex 1
• Polycomb-Group Proteins (physiology)
• Protein Processing, Post-Translational
• Proteins (physiology)
• Receptors, Notch (genetics, metabolism)
• Signal Transduction
• Spheroids, Cellular (metabolism)
• Tumor Burden