The zinc finger transcription factor ZFX is required for maintaining the tumorigenic potential of glioblastoma stem cells.
Glioblastomas are highly lethal brain tumors containing tumor-propagating glioma stem cells (GSCs). The molecular mechanisms underlying the maintenance of the GSC phenotype are not fully defined. Here we demonstrate that the zinc finger and X-linked transcription factor (ZFX) maintains GSC self-renewal and tumorigenic potential by upregulating c-Myc expression. ZFX is differentially expressed in GSCs relative to non-stem glioma cells and neural progenitor cells. Disrupting ZFX by shRNA reduced c-Myc expression and potently inhibited GSC self-renewal and tumor growth. Ectopic expression of c-Myc to its endogenous level rescued the effects caused by ZFX disruption, supporting that ZFX controls GSC properties through c-Myc. Furthermore, ZFX binds to a specific sequence (GGGCCCCG) on the human c-Myc promoter to upregulate c-Myc expression. These data demonstrate that ZFX functions as a critical upstream regulator of c-Myc and plays essential roles in the maintenance of the GSC phenotype. This study also supports that c-Myc is a dominant driver linking self-renewal to malignancy.
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Xiaoguang
X
Fang
Zhi
Z
Huang
Wenchao
W
Zhou
Qiulian
Q
Wu
Andrew E
AE
Sloan
Gaoliang
G
Ouyang
Roger E
RE
McLendon
Jennifer S
JS
Yu
Jeremy N
JN
Rich
Shideng
S
Bao
D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051741:Kruppel-Like Transcription Factors; C062076:zinc finger protein, X-linked
Cancer stem cell; Glioblastoma; Self-renewal; Tumorigenesis; Zinc finger and X-linked transcription factor; c-Myc