Journal Article

DKFZ-2019-00525

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma.

Lee, C. ; Rudneva, V. A. ; Erkek, S.DKFZ* ; Zapatka, M.DKFZ* ; Chau, L. Q. ; Tacheva-Grigorova, S. K. ; Garancher, A. ; Rusert, J. M. ; Aksoy, O. ; Lea, R. ; Mohammad, H. P. ; Wang, J. ; Weiss, W. A. ; Grimes, H. L. ; Pfister, S. M. ; Northcott, P. A. ; Wechsler-Reya, R. J.

2019
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-018-08269-5

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.

Keyword(s): Antibiotics, Antineoplastic ; DNA-Binding Proteins ; GFI1 protein, human ; Transcription Factors ; Doxorubicin ; Aof2 protein, mouse ; Histone Demethylases

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)
2. Molekulare Genetik (B060)
3. DKTK Heidelberg (L101)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2019

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