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

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.

SUBMITTER: Chudnovsky Y

PROVIDER: S-EPMC4041390 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Chudnovsky Yakov Y Kim Dohoon D Zheng Siyuan S Whyte Warren A WA Bansal Mukesh M Bray Mark-Anthony MA Gopal Shuba S Theisen Matthew A MA Bilodeau Steve S Thiru Prathapan P Muffat Julien J Yilmaz Omer H OH Mitalipova Maya M Woolard Kevin K Lee Jeongwu J Nishimura Riko R Sakata Nobuo N Fine Howard A HA Carpenter Anne E AE Silver Serena J SJ Verhaak Roel G W RG Califano Andrea A Young Richard A RA Ligon Keith L KL Mellinghoff Ingo K IK Root David E DE Sabatini David M DM Hahn William C WC Chheda Milan G MG

Cell reports 20140116 2

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 ...[more]

PMID: 24440720

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Project description:BackgroundsThe NuRD (Nucleosome Remodeling and Deacetylation) complex is a repressive complex in gene transcription by modulating chromatin accessibility of target genes to transcription factors and RNA polymerase II. Although individual subunits of the complex have been implicated in many other cancer types, the complex's role in human hepatocellular carcinoma (HCC) is not fully understood. More importantly, the NuRD complex has not yet been investigated as a whole in cancers.MethodsWe analyzed the expression of the NuRD complex in HCC and evaluated the prognostic value of NuRD complex expression in HCC using the RNA-seq data obtained from the TCGA project. We examined the effect of CHD4 knockdown on HCC cell proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition, colony-forming ability, and on complement gene expression. We also performed bioinformatic analyses to investigate the correlation between the NuRD complex expression and immune infiltration.ResultsWe found that nine subunits, out of 14 subunits of the NuRD complex examined, were significantly overexpressed in HCC, and their expression levels were positively correlated with cancer progression. More importantly, our data also demonstrated that these subunits tended to be overexpressed as a whole in HCC. Subsequent studies demonstrated that knockdown of CHD4 in HCC cells inhibits cell proliferation, migration, invasion, and colony-forming ability and promotes apoptosis of HCC cells, indicating that the CHD4/NuRD complex plays oncogenic roles in HCC. Further analysis revealed that the CHD4/NuRD complex regulates complement gene expression in HCC. Intriguingly, we found that the CHD4/NuRD complex expression was inversely correlated with CD8 T cell infiltration in HCC.ConclusionsOur data demonstrate that the CHD4/NuRD complex plays an oncogenic role in human HCC and regulates complement gene expression in HCC cells. The results of inverse correlation between the CHD4/NuRD complex and CD8 T cell and DC cell infiltration in HCC suggest that the CHD4/NuRD complex not only plays direct regulatory roles in HCC cells, but also has an impact on the immune microenvironment of HCC.

Dataset Information

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

Publications

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

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