Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Catherine Lee, Vasilisa A. Rudneva, Serap Erkek, Marc Zapatka, Lianne Q. Chau, Silvia K. Tacheva-Grigorova, Alexandra Garancher, Jessica M. Rusert, Ozlem Aksoy, Robin Lea, Helai P. Mohammad, Jianxun Wang, William A. Weiss, H. Leighton Grimes, Stefan M. Pfister, Paul A. Northcott, Robert J. Wechsler-Reya

ABSTRACT

Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis, and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma. More... »

PAGES

332

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-08269-5

    DOI

    http://dx.doi.org/10.1038/s41467-018-08269-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1111514315

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30659187


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    464 https://www.grid.ac/institutes/grid.7497.d schema:alternateName German Cancer Research Center
    465 schema:name Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
    466 Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
    467 Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117, Heidelberg, Germany
    468 Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany
    469 rdf:type schema:Organization
     




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