Xu L1, Chen Y2, Mayakonda A2, Koh L3,4, Chong YK3, Buckley DL5, Sandanaraj E3,4,6, Lim SW3, Lin RY2, Ke XY2, Huang ML2,7, Chen J8, Sun W4, Wang LZ2,9, Goh BC2,9,10, Dinh HQ11, Kappei D2, Winter GE5, Ding LW2, Ang BT6,12,13,14, Berman BP11, Bradner JE5,15, Tang C3,8,13, Koeffler HP2,10,16.
1Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore.
2Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore.
3Department of Research, National Neuroscience Institute, 308433 Singapore.
4School of Biological Sciences, Nanyang Technological University, 637551 Singapore.
5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
6Singapore Institute for Clinical Sciences, Agency for Science, Technology, and Research, 117609 Singapore.
7School of Biology and Basic Medical Sciences, Soochow University, 215123 Suzhou, China.
8Humphrey Oei Institute of Cancer Research, National Cancer Centre, 169610 Singapore.
9Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore.
10National University Cancer Institute, National University Hospital, 119074 Singapore.
11Center for Bioinformatics and Functional Genomics, Biomedical Sciences, Cedars-Sinai Medical Center, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90048.
12Department of Neurosurgery, National Neuroscience Institute, 308433 Singapore.
13Duke-National University of Singapore Medical School, 169857 Singapore.
14Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117593 Singapore.
15Department of Medicine, Harvard Medical School, Boston, MA 02115.
16Division of Hematology/Oncology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048.
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 proteinsin GBM.
BRD2; BRD3; BRD4; E2F; glioma