Abstract
Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.
Original language | American English |
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Pages (from-to) | E5086-E5095 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 115 |
Issue number | 22 |
DOIs | |
State | Published - 29 May 2018 |
Externally published | Yes |
Bibliographical note
Funding Information:We thank Nathanael S. Gray, Jinhua Wang, Tinghu Zhang, Lavina Tay, Shwu-Yuan Wu, and Cheng-Ming Chiang for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse work. We are grateful to Bing Ren, Sudhakar Jha, Fang Hu, and members of the H.P.K. laboratory for kind discussions and suggestions. This work is funded by the National Research Foundation Singapore under the Singapore Translational Research Investigator Award NMRC/STaR/0021/2014 (to H.P.K.); the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150 and MOE2017-T2-1-033); the Singapore Ministry of Health’s National Medical Research Council (NMRC) Centre Grant awarded to National University Cancer Institute of Singapore (NCIS), the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Cen-tres of Excellence initiatives; and is additionally supported by a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and philanthropic donations from the Melamed family, Aaron Eshman, and Valerie Baker Fair-bank who deeply inspires our work. B.T.A. and C.T. are supported by an NMRC Translational & Clinical Research Flagship Programme Grant (NMRC/ TCR/016-NNI/2016). D.L.B. was supported by the Damon Runyon Cancer Research Foundation as a Merck Fellow (DRG-2196-14). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg).
Funding Information:
ACKNOWLEDGMENTS. We thank Nathanael S. Gray, Jinhua Wang, Tinghu Zhang, Lavina Tay, Shwu-Yuan Wu, and Cheng-Ming Chiang for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse work. We are grateful to Bing Ren, Sudhakar Jha, Fang Hu, and members of the H.P.K. laboratory for kind discussions and suggestions. This work is funded by the National Research Foundation Singapore under the Singapore Translational Research Investigator Award NMRC/STaR/0021/2014 (to H.P.K.); the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150 and MOE2017-T2-1-033); the Singapore Ministry of Health’s National Medical Research Council (NMRC) Centre Grant awarded to National University Cancer Institute of Singapore (NCIS), the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Centres of Excellence initiatives; and is additionally supported by a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and philanthropic donations from the Melamed family, Aaron Eshman, and Valerie Baker Fair-bank who deeply inspires our work. B.T.A. and C.T. are supported by an NMRC Translational & Clinical Research Flagship Programme Grant (NMRC/ TCR/016-NNI/2016). D.L.B. was supported by the Damon Runyon Cancer Research Foundation as a Merck Fellow (DRG-2196-14). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg).
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
Keywords
- BRD2
- BRD3
- BRD4
- E2F
- Glioma