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.
American Cancer Society (Postdoctoral Fellowship)
American Brain Tumor Association (Discovery Grant)
National Institutes of Health (U.S.) (Grant P30CA016672)
National Institutes of Health (U.S.) (Grant U24CA143883)
European Leukodystrophy Association
Japan. Ministry of Education, Culture, Sports, Science and Technology (MEXT/JSPS (KAKENHI 256701)
Broad Institute of MIT and Harvard
National Institutes of Health (U.S.) (NIH (R01GM089652)
National Institutes of Health (U.S.) (NIH (U01CA168426)
National Institutes of Health (U.S.) (NIH U54CA121852)
National Institutes of Health (U.S.) (NIH (R01HG002668)
National Institutes of Health (U.S.) (NIH R01CA146455)
National Institutes of Health (U.S.) (NIH (R01CA170592)
National Institutes of Health (U.S.) (NIH P01CA095616)
Sontag Foundation
Goldhirsh Foundation
National Institutes of Health (U.S.) (NIH R01NS080944)
Starr Foundation
National Institutes of Health (U.S.) (NIH (R01CA129105)
David H. Koch Institute for Integrative Cancer Research at MIT
National Institutes of Health (U.S.) (NIH P01CA142536)
National Institutes of Health (U.S.) (NIH U01CA176058)
National Institutes of Health (U.S.) (NIH K08NS062907)
National Institutes of Health (U.S.) (NIH K12CA090354)
American Association for Cancer Research
National Brain Tumor Society (fellowship)
Dana-Farber Cancer Institute (Pediatric Low Grade Astrocytoma Program grant)
Broad Institute of MIT and Harvard (SPARC grant)
Howard Hughes Medical Institute (Investigator)