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dc.contributor.authorYoon, Jeehyunen_US
dc.contributor.authorGrinchuk, Oleg V.en_US
dc.contributor.authorKannan, Srinivasaraghavanen_US
dc.contributor.authorAng, Melgious Jin Yanen_US
dc.contributor.authorLi, Zhenglinen_US
dc.contributor.authorTay, Emmy Xue Yunen_US
dc.contributor.authorLok, Ker Zhingen_US
dc.contributor.authorLee, Bernice Woon Lien_US
dc.contributor.authorChuah, You Hengen_US
dc.contributor.authorChia, Kimberlyen_US
dc.contributor.authorTirado-Magallanes, Robertoen_US
dc.contributor.authorLiu, Chenfeien_US
dc.contributor.authorZhao, Haonanen_US
dc.contributor.authorHor, Jin Huien_US
dc.contributor.authorLim, Jhin Jiehen_US
dc.contributor.authorBenoukraf, Touatien_US
dc.contributor.authorToh, Tan Boonen_US
dc.contributor.authorChow, Edward Kai-Huaen_US
dc.contributor.authorKovalik, Jean-Paulen_US
dc.contributor.authorChing, Jianhongen_US
dc.contributor.authorNg, Shi-Yanen_US
dc.contributor.authorKoh, Ming Jooen_US
dc.contributor.authorLiu, Xiaogangen_US
dc.contributor.authorVerma, Chandra Shekharen_US
dc.contributor.authorOng, Derrick Sek Tongen_US
dc.identifier.citationYoon, J., Grinchuk, O. V., Kannan, S., Ang, M. J. Y., Li, Z., Tay, E. X. Y., Lok, K. Z., Lee, B. W. L., Chuah, Y. H., Chia, K., Tirado-Magallanes, R., Liu, C., Zhao, H., Hor, J. H., Lim, J. J., Benoukraf, T., Toh, T. B., Chow, E. K., Kovalik, J., ...Ong, D. S. T. (2021). A chemical biology approach reveals a dependency of glioblastoma on biotin distribution. Science Advances, 7(36), eabf6033-.
dc.description.abstractGlioblastoma (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.en_US
dc.description.sponsorshipNational Research Foundation (NRF)en_US
dc.description.sponsorshipNational University of Singapore (NUS), Temasek Laboratoriesen_US
dc.relation.ispartofScience Advancesen_US
dc.rights© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).en_US
dc.subjectScience::Biological sciencesen_US
dc.titleA chemical biology approach reveals a dependency of glioblastoma on biotin distributionen_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.contributor.organizationNational University of Singaporeen_US
dc.contributor.organizationDuke-NUS Medical Schoolen_US
dc.contributor.organizationNational Neuroscience Instituteen_US
dc.description.versionPublished versionen_US
dc.subject.keywordsReceptor-Mediated Endocytosisen_US
dc.description.acknowledgementThis work was supported by the National Research Foundation Fellowship NRF-NRFF2017-01 (D.S.T.O.), National University of Singapore (NUS) start-up grant (D.S.T.O. and M.J.K.), NUS President’s Assistant Professorship (D.S.T.O.), and NUS Research Scholarships (M.J.Y.A., B.W.L.L., Y.H.C., and R.T.M.). S.K. and C.S.V. thank A*STAR and NSCC for support.en_US
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