A chemical biology approach reveals a dependency of glioblastoma on biotin distribution.

Autor: Yoon J; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Grinchuk OV; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Kannan S; Biomolecular Modeling and Design Division, Bioinformatics Institute, A*STAR (Agency for Science, Technology and Research), Singapore 138671, Singapore., Ang MJY; Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore 119077, Singapore., Li Z; Department of Chemistry, National University of Singapore, Singapore 117543, Singapore., Tay EXY; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Lok KZ; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Lee BWL; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Chuah YH; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Chia K; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Tirado Magallanes R; Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore., Liu C; Department of Chemistry, National University of Singapore, Singapore 117543, Singapore., Zhao H; Department of Chemistry, National University of Singapore, Singapore 117543, Singapore., Hor JH; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore , Singapore., Lim JJ; Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore., Benoukraf T; Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.; Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada., Toh TB; The N.1 Institute for Health, National University of Singapore, Singapore , Singapore.; Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Chow EK; Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore., Kovalik JP; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore., Ching J; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore., Ng SY; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore , Singapore.; National Neuroscience Institute, Singapore 308433, Singapore., Koh MJ; Department of Chemistry, National University of Singapore, Singapore 117543, Singapore., Liu X; Department of Chemistry, National University of Singapore, Singapore 117543, Singapore., Verma CS; Biomolecular Modeling and Design Division, Bioinformatics Institute, A*STAR (Agency for Science, Technology and Research), Singapore 138671, Singapore.; Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore., Ong DST; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore , Singapore.; National Neuroscience Institute, Singapore 308433, Singapore.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Sep 03; Vol. 7 (36), pp. eabf6033. Date of Electronic Publication: 2021 Sep 03.
DOI: 10.1126/sciadv.abf6033
Abstrakt: Glioblastoma (GBM) is a uniformly lethal disease driven by glioma stem cells (GSCs). Here, we use a chemical biology approach to unveil previously unknown GBM dependencies. By studying sulconazole (SN) with anti-GSC properties, we find that SN disrupts biotin distribution to the carboxylases and histones. Transcriptomic and metabolomic analyses of SN-treated GSCs reveal metabolic alterations that are characteristic of biotin-deficient cells, including intracellular cholesterol depletion, impairment of oxidative phosphorylation, and energetic crisis. Furthermore, SN treatment reduces histone biotinylation, histone acetylation, and expression of superenhancer-associated GSC critical genes, which are also observed when biotin distribution is genetically disrupted by holocarboxylase synthetase ( HLCS ) depletion. HLCS silencing impaired GSC tumorigenicity in an orthotopic xenograft brain tumor model. In GBM, high HLCS expression robustly indicates a poor prognosis. Thus, the dependency of GBM on biotin distribution suggests that the rational cotargeting of biotin-dependent metabolism and epigenetic pathways may be explored for GSC eradication.
Databáze: MEDLINE