title: Nestin Mediates Hedgehog Pathway Tumorigenesis.
abstract: The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here, we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation, resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Cancer Res; 76(18); 5573-83. ©2016 AACR.
authors: Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors: Peng
authors: P
authors: Li
authors: Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors: Eric H
authors: EH
authors: Lee
authors: Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors: Fang
authors: F
authors: Du
authors: Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors: Renata E
authors: RE
authors: Gordon
authors: Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors: Larra W
authors: LW
authors: Yuelling
authors: Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors: Yongqiang
authors: Y
authors: Liu
authors: Children's Research Institute, Children's Mercy Kansas City, Kansas City, Missouri.
authors: Jessica M Y
authors: JM
authors: Ng
authors: Molecular Therapeutics Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors: Hao
authors: H
authors: Zhang
authors: Molecular Therapeutics Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors: Jinhua
authors: J
authors: Wu
authors: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Andrey
authors: A
authors: Korshunov
authors: Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Heidelberg University Hospital, Heidelberg, Germany.
authors: Stefan M
authors: SM
authors: Pfister
authors: Children's Research Institute, Children's Mercy Kansas City, Kansas City, Missouri.
authors: Tom
authors: T
authors: Curran
authors: Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania. zengjie.yang@fccc.edu.
authors: Zeng-Jie
authors: ZJ
authors: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D042282:Microdissection; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D064231:Nestin / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D000074290:Zinc Finger Protein Gli3
chemical_list: C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D000074290:Zinc Finger Protein Gli3