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Title: A chemical biology approach reveals a dependency of glioblastoma on biotin distribution
Authors: Yoon, Jeehyun
Grinchuk, Oleg V.
Kannan, Srinivasaraghavan
Ang, Melgious Jin Yan
Li, Zhenglin
Tay, Emmy Xue Yun
Lok, Ker Zhing
Lee, Bernice Woon Li
Chuah, You Heng
Chia, Kimberly
Tirado-Magallanes, Roberto
Liu, Chenfei
Zhao, Haonan
Hor, Jin Hui
Lim, Jhin Jieh
Benoukraf, Touati
Toh, Tan Boon
Chow, Edward Kai-Hua
Kovalik, Jean-Paul
Ching, Jianhong
Ng, Shi-Yan
Koh, Ming Joo
Liu, Xiaogang
Verma, Chandra Shekhar
Ong, Derrick Sek Tong
Keywords: Science::Biological sciences
Issue Date: 2021
Source: Yoon, 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-.
Project: NRF-NRFF2017-01
Journal: Science Advances 
Abstract: 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.
ISSN: 2375-2548
DOI: 10.1126/sciadv.abf6033
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).
Fulltext Permission: open
Fulltext Availability: With Fulltext
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