| Literature DB >> 29764999 |
Liang Xu1, Ye Chen2, Anand Mayakonda2, Lynnette Koh3,4, Yuk Kien Chong3, Dennis L Buckley5, Edwin Sandanaraj3,4,6, See Wee Lim3, Ruby Yu-Tong Lin2, Xin-Yu Ke2, Mo-Li Huang2,7, Jianxiang Chen8, Wendi Sun4, Ling-Zhi Wang2,9, Boon Cher Goh2,9,10, Huy Q Dinh11, Dennis Kappei2, Georg E Winter5, Ling-Wen Ding2, Beng Ti Ang6,12,13,14, Benjamin P Berman11, James E Bradner5,15, Carol Tang3,8,13, H Phillip Koeffler2,10,16.
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.Entities:
Keywords: BRD2; BRD3; BRD4; E2F; glioma
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Year: 2018 PMID： 29764999 PMCID： PMC5984485 DOI： 10.1073/pnas.1712363115
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205