title: Kruppel-like factor-9 (KLF9) inhibits glioblastoma stemness through global transcription repression and integrin α6 inhibition.
abstract: It is increasingly important to understand the molecular basis for the plasticity of neoplastic cells and their capacity to transition between differentiated and stemlike phenotypes. Kruppel-like factor-9 (KLF9), a member of the large KLF transcription factor family, has emerged as a regulator of oncogenesis, cell differentiation, and neural development; however, the molecular basis for the diverse contextual functions of KLF9 remains unclear. This study focused on the functions of KLF9 in human glioblastoma stemlike cells. We established for the first time a genome-wide map of KLF9-regulated targets in human glioblastoma stemlike cells and show that KLF9 functions as a transcriptional repressor and thereby regulates multiple signaling pathways involved in oncogenesis and stem cell regulation. A detailed analysis of one such pathway, integrin signaling, showed that the capacity of KLF9 to inhibit glioblastoma cell stemness and tumorigenicity requires ITGA6 repression. These findings enhance our understanding of the transcriptional networks underlying cancer cell stemness and differentiation and identify KLF9-regulated molecular targets applicable to cancer therapeutics.
authors.affiliation: From the Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, Departments of Neurology.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Ying
authors.affiliation: From the Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, Neuroscience.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tilghman
authors.affiliation: Department of Statistics, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205.
authors.forename: Hugo
authors.initials: H
authors.lastname: Guerrero-Cazares
authors.affiliation: Neuroscience, Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, Oncology, and.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Quinones-Hinojosa
authors.affiliation: Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, 21205, and.
authors.forename: Hongkai
authors.initials: H
authors.lastname: Ji
authors.affiliation: From the Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, Departments of Neurology, Neuroscience, Oncology, and laterra@kennedykrieger.org.
authors.forename: John
authors.initials: J
authors.lastname: Laterra
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D039503:Integrin alpha6 / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016513:Mice, SCID; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D039503:Integrin alpha6; C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D004317:Doxorubicin
keywords: Cancer Stem Cells; ChIP-Sequencing (ChIP-Seq); Glioblastoma; Kruppel-like Factor (KLF); Transcription Repressor