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
Affiliations
Chi-Yeh Chung
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Zhen Sun
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Gavriel Mullokandov
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Almudena Bosch
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Zulekha A. Qadeer
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Esma Cihan
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Zachary Rapp
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Ramon Parsons
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Julio A. Aguirre-Ghiso
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Eduardo F. Farias
Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Brian D. Brown
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Alexandre Gaspar-Maia
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
Emily Bernstein
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
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.
