Cell Reports (Jan 2014)
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
Affiliations
- Yakov Chudnovsky
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Dohoon Kim
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Siyuan Zheng
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
- Warren A. Whyte
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Mukesh Bansal
- Department of Systems Biology, Columbia University, New York, NY 10032, USA
- Mark-Anthony Bray
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Shuba Gopal
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Matthew A. Theisen
- Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Steve Bilodeau
- Centre de Recherche sur le Cancer and Centre de Recherche du CHU de Québec (Hôtel-Dieu de Québec), Université Laval, QC G1R 2J6, Canada
- Prathapan Thiru
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Julien Muffat
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Omer H. Yilmaz
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Maya Mitalipova
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Kevin Woolard
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA
- Jeongwu Lee
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, OH 44195, USA
- Riko Nishimura
- Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan
- Nobuo Sakata
- Department of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan
- Howard A. Fine
- Division of Hematology and Medical Oncology, New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016, USA
- Anne E. Carpenter
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Serena J. Silver
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Roel G.W. Verhaak
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
- Andrea Califano
- Department of Systems Biology, Columbia University, New York, NY 10032, USA
- Richard A. Young
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Keith L. Ligon
- Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Ingo K. Mellinghoff
- Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- David E. Root
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- David M. Sabatini
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- William C. Hahn
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Milan G. Chheda
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- DOI
- https://doi.org/10.1016/j.celrep.2013.12.032
- Journal volume & issue
-
Vol. 6,
no. 2
pp. 313 – 324
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.
