A chemical biology approach reveals a dependency of glioblastoma on biotin distribution
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 his...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/154365 |
| _version_ | 1826117294151958528 |
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| author | 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 |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences 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 |
| author_sort | Yoon, Jeehyun |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:25:16Z |
| format | Journal Article |
| id | ntu-10356/154365 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:25:16Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1543652023-02-28T17:11:32Z A chemical biology approach reveals a dependency of glioblastoma on biotin distribution 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 School of Biological Sciences National University of Singapore A*STAR Duke-NUS Medical School National Neuroscience Institute Science::Biological sciences Receptor-Mediated Endocytosis Gene-Expression 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. National Research Foundation (NRF) National University of Singapore (NUS), Temasek Laboratories Published version This 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. 2022-04-07T05:50:32Z 2022-04-07T05:50:32Z 2021 Journal Article 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-. https://dx.doi.org/10.1126/sciadv.abf6033 2375-2548 https://hdl.handle.net/10356/154365 10.1126/sciadv.abf6033 34516894 2-s2.0-85114355505 36 7 eabf6033 en NRF-NRFF2017-01 Science Advances © 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). application/pdf |
| spellingShingle | Science::Biological sciences Receptor-Mediated Endocytosis Gene-Expression 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 A chemical biology approach reveals a dependency of glioblastoma on biotin distribution |
| title | A chemical biology approach reveals a dependency of glioblastoma on biotin distribution |
| title_full | A chemical biology approach reveals a dependency of glioblastoma on biotin distribution |
| title_fullStr | A chemical biology approach reveals a dependency of glioblastoma on biotin distribution |
| title_full_unstemmed | A chemical biology approach reveals a dependency of glioblastoma on biotin distribution |
| title_short | A chemical biology approach reveals a dependency of glioblastoma on biotin distribution |
| title_sort | chemical biology approach reveals a dependency of glioblastoma on biotin distribution |
| topic | Science::Biological sciences Receptor-Mediated Endocytosis Gene-Expression |
| url | https://hdl.handle.net/10356/154365 |
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