Author:
Phillips Richard E.,Yang Yanhong,Smith Ryan C.,Thompson Bonne M.,Yamasaki Tomoko,Soto-Feliciano Yadira M.,Funato Kosuke,Liang Yupu,Garcia-Bermudez Javier,Wang Xiaoshi,Garcia Benjamin A.,Yamasaki Kazuhiko,McDonald Jeffrey G.,Birsoy Kivanç,Tabar Viviane,Allis C. David
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.
Publisher
Proceedings of the National Academy of Sciences
Cited by
47 articles.
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