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

Proceedings of the National Academy of Sciences of the United States of America
Liang XuH Phillip Koeffler

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.

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Citations

Jul 12, 2019·Bioscience Reports·Xiaojian LiLiangsheng Luo
Aug 11, 2019·Nature Communications·Melanie Si Yan TanCarol Tang
Oct 18, 2019·Acta Neuropathologica Communications·Mirca S Saurty-SeerunghenMarie-Pierre Junier
Oct 14, 2020·Proceedings of the National Academy of Sciences of the United States of America·Karishma PatelJoel P Mackay
Nov 29, 2020·Protein Science : a Publication of the Protein Society·Karishma PatelJoel P Mackay
Mar 7, 2021·International Journal of Molecular Sciences·Tiziana ServideiRiccardo Riccardi
Apr 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·Najla KfouryJoshua B Rubin
Apr 15, 2021·Molecular Therapy Oncolytics·Hua YangHua You
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Jun 4, 2021·Science Advances·Juan WangAmanda Saratsis
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Dec 5, 2021·Scientific Reports·Anna M JermakowiczNagi G Ayad
Apr 11, 2020·Anti-cancer Agents in Medicinal Chemistry·Samir H Barghout

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