title: 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.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Chi-Yeh
authors.initials: CY
authors.lastname: Chung
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Gavriel
authors.initials: G
authors.lastname: Mullokandov
authors.affiliation: 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.
authors.forename: Almudena
authors.initials: A
authors.lastname: Bosch
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Zulekha A
authors.initials: ZA
authors.lastname: Qadeer
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Esma
authors.initials: E
authors.lastname: Cihan
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Rapp
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
authors.affiliation: Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; 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.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
authors.affiliation: 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.
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Farias
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Brown
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: alexandre.maia@mssm.edu.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gaspar-Maia
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: emily.bernstein@mssm.edu.
authors.forename: Emily
authors.initials: E
authors.lastname: Bernstein
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000502:physiology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D033681:Mitochondrial Membrane Transport Proteins; D063146:Polycomb-Group Proteins; D011506:Proteins; D051880:Receptors, Notch; C443118:Wdr5 protein, mouse; C570429:Cbx8 protein, mouse; D063150:Polycomb Repressive Complex 1