ZFHX4 Interacts with the NuRD Core Member CHD4 and Regulates the Glioblastoma Tumor-Initiating Cell State

• Published in: Cell reports (Cambridge) Vol. 6; no. 2; pp. 313 - 324
• Main Authors: Chudnovsky, Yakov, Kim, Dohoon, Zheng, Siyuan, Whyte, Warren A., Bansal, Mukesh, Bray, Mark-Anthony, Gopal, Shuba, Theisen, Matthew A., Bilodeau, Steve, Thiru, Prathapan, Muffat, Julien, Yilmaz, Omer H., Mitalipova, Maya, Woolard, Kevin, Lee, Jeongwu, Nishimura, Riko, Sakata, Nobuo, Fine, Howard A., Carpenter, Anne E., Silver, Serena J., Verhaak, Roel G.W., Califano, Andrea, Young, Richard A., Ligon, Keith L., Mellinghoff, Ingo K., Root, David E., Sabatini, David M., Hahn, William C., Chheda, Milan G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2014; Elsevier
• Subjects: 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
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.12.032

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. [Display omitted] •An image-based screen identifies regulators of glioblastoma tumor-initiating cells•ZFHX4 is required for the glioblastoma tumor-initiating cell state•ZFHX4 interacts with and regulates CHD4, a core member of the NuRD complex•ZFHX4 and CHD4 colocalize throughout the genome and coregulate gene expression Glioblastoma (GBM), the most common and aggressive primary brain tumor, contains a subpopulation of stem cell-like, therapy-resistant tumor-initiating cells (TICs). Sabatini, Hahn, and colleagues performed an image-based RNAi screen in order to identify candidate regulators of GBM TIC functions. ZFHX4, identified in this screen, is essential for the stem cell-like state and tumorigenicity of TICs. Additionally, ZFHX4 interacts with CHD4, a core member of the chromatin regulatory NuRD complex, and drives CHD4-dependent gene expression programs.