title: A complex of nuclear factor I-X3 and STAT3 regulates astrocyte and glioma migration through the secreted glycoprotein YKL-40.
abstract: Nuclear factor I-X3 (NFI-X3) is a newly identified splice variant of NFI-X that regulates expression of several astrocyte-specific markers, such as glial fibrillary acidic protein. Here, we identified a set of genes regulated by NFI-X3 that includes a gene encoding a secreted glycoprotein YKL-40. Although YKL-40 expression is up-regulated in glioblastoma multiforme, its regulation and functions in nontransformed cells of the central nervous system are widely unexplored. We find that expression of YKL-40 is activated during brain development and also differentiation of neural progenitors into astrocytes in vitro. Furthermore, YKL-40 is a migration factor for primary astrocytes, and its expression is controlled by both NFI-X3 and STAT3, which are known regulators of gliogenesis. Knockdown of NFI-X3 and STAT3 significantly reduced YKL-40 expression in astrocytes, whereas overexpression of NFI-X3 dramatically enhanced YKL-40 expression in glioma cells. Activation of STAT3 by oncostatin M induced YKL-40 expression in astrocytes, whereas expression of a dominant-negative STAT3 had a suppressive effect. Mechanistically, NFI-X3 and STAT3 form a complex that binds to weak regulatory elements in the YKL-40 promoter and activates transcription. We propose that NFI-X3 and STAT3 control the migration of differentiating astrocytes as well as migration and invasion of glioma cells via regulating YKL-40 expression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Singh
authors.forename: Reetika
authors.initials: R
authors.lastname: Bhardwaj
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Wilczynska
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Dumur
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kordula
mesh_terms: D054392:Adipokines / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D000071451:Chitinase-3-Like Protein 1; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D037102:Lectins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D053683:Oncostatin M / Q000378:metabolism / Q000494:pharmacology; D020218:Response Elements / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; C077305:CTF-1 transcription factor; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D046912:Multiprotein Complexes; D051839:NFI Transcription Factors; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053683:Oncostatin M