Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma

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 and Robert J. Wechsler-Reya ()
Additional contact information
Catherine Lee: NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
Vasilisa A. Rudneva: St. Jude Children’s Research Hospital
Serap Erkek: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Marc Zapatka: German Cancer Research Center (DKFZ)
Lianne Q. Chau: NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
Silvia K. Tacheva-Grigorova: NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
Alexandra Garancher: NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
Jessica M. Rusert: NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
Ozlem Aksoy: University of California
Robin Lea: University of California
Helai P. Mohammad: GlaxoSmithKline
Jianxun Wang: Beijing University of Chinese Medicine
William A. Weiss: University of California
H. Leighton Grimes: Cincinnati Children’s Hospital Medical Center
Stefan M. Pfister: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Paul A. Northcott: St. Jude Children’s Research Hospital
Robert J. Wechsler-Reya: NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-08269-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08269-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-08269-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().