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Nat Commun. 2019 Jan 18;10(1):332. doi: 10.1038/s41467-018-08269-5.

Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma.

Author information

1
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
2
Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, 92093, USA.
3
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
4
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, 69120, Germany.
5
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, 69117, Germany.
6
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
7
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
8
Department of Neurology, University of California, San Francisco, CA, 94158, USA.
9
Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, PA, 19426, USA.
10
College of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
11
Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
12
Heidelberg University Hospital, Department of Pediatric Hematology and Oncology, Heidelberg, 69120, Germany.
13
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. rwreya@sbpdiscovery.org.
14
Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, 92093, USA. rwreya@sbpdiscovery.org.

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.

PMID:
30659187
PMCID:
PMC6338772
DOI:
10.1038/s41467-018-08269-5
[Indexed for MEDLINE]
Free PMC Article

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