ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state.
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.
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.
Yakov
Y
Chudnovsky
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Dohoon
D
Kim
Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
Siyuan
S
Zheng
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Warren A
WA
Whyte
Department of Systems Biology, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.
Mukesh
M
Bansal
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Mark-Anthony
MA
Bray
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Shuba
S
Gopal
Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Matthew A
MA
Theisen
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.
Steve
S
Bilodeau
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Prathapan
P
Thiru
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Julien
J
Muffat
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.
Omer H
OH
Yilmaz
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Maya
M
Mitalipova
Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
Kevin
K
Woolard
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, OH 44195, USA.
Jeongwu
J
Lee
Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
Riko
R
Nishimura
Department of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
Nobuo
N
Sakata
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.
Howard A
HA
Fine
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Anne E
AE
Carpenter
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Serena J
SJ
Silver
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.
Roel G W
RG
Verhaak
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.
Andrea
A
Califano
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Richard A
RA
Young
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.
Keith L
KL
Ligon
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.
Ingo K
IK
Mellinghoff
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
David E
DE
Root
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.
David M
DM
Sabatini
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.
William C
WC
Hahn
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.
Milan G
MG
Chheda
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism*; D016688:Mice, Inbred NOD; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D001324:Autoantigens; C115323:CHD4 protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; C000591861:ZFHX4 protein, human; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex