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

被引：99

作者：

Chudnovsky, Yakov ^{[1
,2
,3
]}

Kim, Dohoon ^{[1
,2
]}

Zheng, Siyuan ^{[4
]}

Whyte, Warren A. ^{[1
]}

Bansal, Mukesh ^{[5
,6
]}

Bray, Mark-Anthony ^{[3
]}

Gopal, Shuba ^{[3
]}

Theisen, Matthew A. ^{[7
]}

Bilodeau, Steve ^{[8
,9
,10
]}

Thiru, Prathapan ^{[1
]}

Muffat, Julien ^{[1
]}

Yilmaz, Omer H. ^{[1
,2
,11
]}

Mitalipova, Maya ^{[1
]}

Woolard, Kevin ^{[12
]}

Lee, Jeongwu ^{[13
]}

Nishimura, Riko ^{[14
]}

Sakata, Nobuo ^{[15
]}

Fine, Howard A. ^{[16
,17
]}

Carpenter, Anne E. ^{[3
]}

Silver, Serena J. ^{[3
]}

Verhaak, Roel G. W. ^{[4
,18
]}

Califano, Andrea ^{[5
,6
,19
,20
,21
,22
]}

Young, Richard A. ^{[1
,2
]}

Ligon, Keith L. ^{[7
,23
,24
]}

Mellinghoff, Ingo K. ^{[25
,26
,27
]}

Root, David E. ^{[3
]}

Sabatini, David M. ^{[1
,2
,3
,11
,28
]}

Hahn, William C. ^{[3
,29
,30
]}

Chheda, Milan G. ^{[3
,25
,26
,29
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] MIT, Dept Biol, Cambridge, MA 02139 USA

[3] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[4] Univ Texas Houston, MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[5] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA

[6] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA

[7] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, Boston, MA 02115 USA

[8] Univ Laval, Hotel Dieu Quebec, CHU Quebec, Ctr Rech Canc, Quebec City, PQ G1R 2J6, Canada

[9] Univ Laval, Hotel Dieu Quebec, CHU Quebec, Ctr Rech, Quebec City, PQ G1R 2J6, Canada

[10] Univ Laval, Fac Med, Dept Biol Mol Biochim Med & Pathol, Quebec City, PQ G1R 2J6, Canada

[11] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[12] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA

[13] Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44195 USA

[14] Osaka Univ, Grad Sch Dent, Dept Mol & Cellular Biochem, Suita, Osaka 5650871, Japan

[15] Showa Pharmaceut Univ, Dept Biochem, Machida, Tokyo 1948543, Japan

[16] NYU, Langone Med Ctr, Inst Canc, Div Hematol & Med Oncol, New York, NY 10016 USA

[17] NYU, Langone Med Ctr, Inst Canc, Brain Tumor Ctr, New York, NY 10016 USA

[18] Univ Texas Houston, MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[19] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA

[20] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA

[21] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA

[22] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA

[23] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[24] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[25] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10065 USA

[26] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[27] Weill Cornell Grad Sch Biomed Sci, Dept Pharmacol, New York, NY 10021 USA

[28] Howard Hughes Med Inst, Cambridge, MA 02139 USA

[29] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[30] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

来源：

CELL REPORTS | 2014年 / 6卷 / 02期

基金：

美国国家卫生研究院;

关键词：

GLIOMA STEM-CELLS; BRAIN-TUMORS; MESENCHYMAL TRANSFORMATION; TRANSCRIPTIONAL NETWORK; PEDIATRIC GLIOBLASTOMA; MALIGNANT GLIOMA; GENE-EXPRESSION; RNAI SCREEN; C-MYC; DIFFERENTIATION;

D O I：

10.1016/j.celrep.2013.12.032

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：313 / 324

页数：12

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