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Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma
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Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma
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Journal Article
Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma
2019
Overview
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.
Medulloblastoma is one of the most prevalent malignant brain tumors in children and has very poor prognosis. In this study, the authors show, using a mouse model of medulloblastoma, that Gfi1 promotes tumor growth by recruiting Lsd1, that this interaction inhibits genes involved in neuronal differentiation, and that Lsd1 may be a therapeutic target in Gfi1-activated tumors.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/2
/ 13/31
/ 38
/ 38/44
/ 42
/ 45
/ 45/15
/ 45/61
/ 59
/ 59/5
/ 64
/ 64/110
/ 64/60
/ 82/80
/ Ablation
/ Animals
/ Antibiotics, Antineoplastic - therapeutic use
/ Cancer
/ Carcinogenesis - drug effects
/ Cell Proliferation - drug effects
/ Cerebellar Neoplasms - genetics
/ Cerebellar Neoplasms - pathology
/ Cerebellar Neoplasms - therapy
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Doxorubicin - therapeutic use
/ Gene Expression Regulation, Neoplastic
/ Histone Demethylases - genetics
/ Histone Demethylases - metabolism
/ Humanities and Social Sciences
/ Humans
/ Lysine
/ Mice
/ Proteins
/ Science
/ Transcription Factors - genetics
/ Transcription Factors - metabolism
/ Tumors
