ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state

Yakov Chudnovsky; Dohoon Kim; Siyuan Zheng; Warren A Whyte; Mukesh Bansal; Mark-Anthony Bray; Shuba Gopal; Matthew A Theisen; Steve Bilodeau; Prathapan Thiru; Julien Muffat; Omer H Yilmaz; Maya Mitalipova; Kevin Woolard; Jeongwu Lee; Riko Nishimura; Nobuo Sakata; Howard A Fine; Anne E Carpenter; Serena J Silver; Roel G W Verhaak; Andrea Califano; Richard A Young; Keith L Ligon; Ingo K Mellinghoff; David E Root; David M Sabatini; William C Hahn; Milan G Chheda

doi:10.1016/j.celrep.2013.12.032

ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state

Cell Rep. 2014 Jan 30;6(2):313-24. doi: 10.1016/j.celrep.2013.12.032. Epub 2014 Jan 16.

Authors

Yakov Chudnovsky¹, Dohoon Kim², Siyuan Zheng³, Warren A Whyte⁴, Mukesh Bansal⁵, Mark-Anthony Bray⁶, Shuba Gopal⁶, Matthew A Theisen⁷, Steve Bilodeau⁸, Prathapan Thiru⁴, Julien Muffat⁴, Omer H Yilmaz⁹, Maya Mitalipova⁴, Kevin Woolard¹⁰, Jeongwu Lee¹¹, Riko Nishimura¹², Nobuo Sakata¹³, Howard A Fine¹⁴, Anne E Carpenter⁶, Serena J Silver⁶, Roel G W Verhaak¹⁵, Andrea Califano¹⁶, Richard A Young², Keith L Ligon¹⁷, Ingo K Mellinghoff¹⁸, David E Root⁶, David M Sabatini¹⁹, William C Hahn²⁰, Milan G Chheda²¹

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
⁵ Department of Systems Biology, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.
⁶ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁷ Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁸ Centre de Recherche sur le Cancer and Centre de Recherche du CHU de Québec (Hôtel-Dieu de Québec), Université Laval, QC G1R 2J6, Canada; Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, QC G1R 2J6, Canada.
⁹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
¹⁰ Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
¹¹ Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, OH 44195, USA.
¹² Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
¹³ Department of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
¹⁴ Division of Hematology and Medical Oncology, New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016, USA; Brain Tumor Center, New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016, USA.
¹⁵ Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ Department of Systems Biology, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
¹⁷ Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁸ Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Pharmacology, Weill-Cornell Graduate School of Biomedical Sciences, New York, NY 10021, USA.
¹⁹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA. Electronic address: sabatini@wi.mit.edu.
²⁰ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: william_hahn@dfci.harvard.edu.
²¹ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Abstract

Glioblastoma (GBM) harbors subpopulations of therapy-resistant tumor-initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397 kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin-remodeling NuRD complex and the GBM TIC state.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoantigens / genetics
Autoantigens / metabolism*
Carcinogenesis / genetics
Carcinogenesis / metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic*
Glioblastoma / genetics
Glioblastoma / metabolism*
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
Mice, Inbred NOD
Protein Binding
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic

Substances

Autoantigens
CHD4 protein, human
Homeodomain Proteins
Transcription Factors
ZFHX4 protein, human
Mi-2 Nucleosome Remodeling and Deacetylase Complex

Abstract

Publication types

MeSH terms

Substances

Grants and funding