Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

Liang Xu*, Ye Chen, Anand Mayakonda, Lynnette Koh, Yuk Kien Chong, Dennis L. Buckley, Edwin Sandanaraj, See Wee Lim, Ruby Yu Tong Lin, Xin Yu Ke, Mo Li Huang, Jianxiang Chen, Wendi Sun, Ling Zhi Wang, Boon Cher Goh, Huy Q. Dinh, Dennis Kappei, Georg E. Winter, Ling Wen Ding, Beng Ti AngBenjamin P. Berman, James E. Bradner, Carol Tang, H. Phillip Koeffler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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 languageAmerican English
Pages (from-to)E5086-E5095
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number22
DOIs
StatePublished - 29 May 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.

Keywords

  • BRD2
  • BRD3
  • BRD4
  • E2F
  • Glioma

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