title: Krüppel-like family of transcription factor 9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma-initiating stem cells.
abstract: Tumor-initiating stem cells (alternatively called cancer stem cells, CSCs) are a subpopulation of tumor cells that plays unique roles in tumor propagation, therapeutic resistance, and tumor recurrence. It is becoming increasingly important to understand the molecular signaling that regulates the self-renewal and differentiation of CSCs. Transcription factors are critical for the regulation of normal and neopolastic stem cells. Here, we examined the expression and function of the Krüppel-like family of transcription factors (KLFs) in human glioblastoma (GBM)-derived neurosphere lines and low-passage primary GBM-derived neurospheres that are enriched for tumor-initiating stem cells. We identify KLF9 as a relatively unique differentiation-induced transcription factor in GBM-derived neurospheres. KLF9 is shown to induce neurosphere cell differentiation, inhibit neurosphere formation, and inhibit neurosphere-derived xenograft growth in vivo. We also show that KLF9 regulates GBM neurosphere cells by binding to the Notch1 promoter and suppressing Notch1 expression and downstream signaling. Our results show for the first time that KLF9 has differentiating and tumor-suppressing functions in tumor-initiating stem cells.
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, USA.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Ying
authors.forename: Yingying
authors.initials: Y
authors.lastname: Sang
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Li
authors.forename: Hugo
authors.initials: H
authors.lastname: Guerrero-Cazares
authors.forename: Alfredo
authors.initials: A
authors.lastname: Quinones-Hinojosa
authors.forename: Angelo L
authors.initials: AL
authors.lastname: Vescovi
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Shuli
authors.initials: S
authors.lastname: Xia
authors.forename: John
authors.initials: J
authors.lastname: Laterra
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1