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Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7957-7962. doi: 10.1073/pnas.1820989116. Epub 2019 Mar 28.

Target identification reveals lanosterol synthase as a vulnerability in glioma.

Author information

1
Department of Neurology and Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
2
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065.
3
Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
4
Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, 305-8566 Tsukuba, Japan.
6
Center for Clinical and Translational Science, The Rockefeller University, New York, NY 10065.
7
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY 10065.
8
Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
9
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065; alliscd@rockefeller.edu.

Abstract

Diffuse intrinsic pontine glioma (DIPG) remains an incurable childhood brain tumor for which novel therapeutic approaches are desperately needed. Previous studies have shown that the menin inhibitor MI-2 exhibits promising activity in preclinical DIPG and adult glioma models, although the mechanism underlying this activity is unknown. Here, using an integrated approach, we show that MI-2 exerts its antitumor activity in glioma largely independent of its ability to target menin. Instead, we demonstrate that MI-2 activity in glioma is mediated by disruption of cholesterol homeostasis, with suppression of cholesterol synthesis and generation of the endogenous liver X receptor ligand, 24,25-epoxycholesterol, resulting in cholesterol depletion and cell death. Notably, this mechanism is responsible for MI-2 activity in both DIPG and adult glioma cells. Metabolomic and biochemical analyses identify lanosterol synthase as the direct molecular target of MI-2, revealing this metabolic enzyme as a vulnerability in glioma and further implicating cholesterol homeostasis as an attractive pathway to target in this malignancy.

KEYWORDS:

MI-2; glioma; lanosterol synthase; menin inhibitor; target identification

PMID:
30923116
PMCID:
PMC6475387
[Available on 2019-09-28]
DOI:
10.1073/pnas.1820989116

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