Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis

Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis

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...

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Main 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
Format: Article
Language:English
Published: Elsevier 2016-07-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124716307215
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spelling doaj-286cd9101ac748d1ab4ec261ff8cbf652020-11-25T01:07:24ZengElsevierCell Reports2211-12472016-07-0116247248610.1016/j.celrep.2016.06.002Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary TumorigenesisChi-Yeh Chung0Zhen Sun1Gavriel Mullokandov2Almudena Bosch3Zulekha A. Qadeer4Esma Cihan5Zachary Rapp6Ramon Parsons7Julio A. Aguirre-Ghiso8Eduardo F. Farias9Brian D. Brown10Alexandre Gaspar-Maia11Emily Bernstein12Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADivision 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, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USAGraduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADivision of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USAChromatin-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.http://www.sciencedirect.com/science/article/pii/S2211124716307215
collection DOAJ
language English
format Article
sources DOAJ
author 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
spellingShingle 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
Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis
Cell Reports
author_facet 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
author_sort Chi-Yeh Chung
title Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis
title_short Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis
title_full Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis
title_fullStr Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis
title_full_unstemmed Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis
title_sort cbx8 acts non-canonically with wdr5 to promote mammary tumorigenesis
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2016-07-01
description 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.
url http://www.sciencedirect.com/science/article/pii/S2211124716307215
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