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Updated: Feb 10, 2026

Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
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Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome

Published on: June 15, 2016

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

Liang Xu1, Ye Chen2, Anand Mayakonda2

  • 1Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore; csixl@nus.edu.sg.

Proceedings of the National Academy of Sciences of the United States of America
|May 17, 2018
PubMed

Insights

Targeted degradation of BET proteins using dBET6 significantly inhibits glioblastoma (GBM) cell proliferation and self-renewal by impacting the E2F1 transcriptional program. This approach offers superior efficacy over traditional inhibitors and overcomes resistance in brain cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BET bromodomain inhibitors (BBIs) show preclinical promise against brain cancers by targeting BET proteins (BRD2, BRD3, BRD4, BRDT).
  • The precise transcriptional network driving glioblastoma (GBM) proliferation via BET proteins remains poorly understood.

Purpose of the Study:

  • To elucidate the role of BET proteins in GBM by investigating a novel chemical degrader, dBET6.
  • To reveal the BET protein-dependent transcriptional network, specifically the E2F1 program, in GBM.

Main Methods:

  • Mechanistic exploration of dBET6, a next-generation chemical degrader of BET proteins.
  • Assessment of dBET6's impact on BET protein genomic occupancy, RNA Polymerase II activity, and chromatin marks.
  • Evaluation of dBET6's effects on GBM cell proliferation, self-renewal, and tumorigenic potential.

Main Results:

  • dBET6 treatment significantly reduced BET protein occupancy, RNA-Pol2 activity, and permissive chromatin marks in GBM cells.
  • dBET6 repressed GBM cell proliferation, self-renewal, and tumorigenic capacity.
  • BET protein degradation via dBET6 demonstrated superior anti-proliferative effects and overcame resistance compared to conventional BBIs.

Conclusions:

  • BET proteins play a crucial role in regulating the E2F1 transcriptional program in both differentiated and initiating GBM cells.
  • Targeted degradation of BET proteins represents a promising therapeutic strategy for GBM, offering enhanced efficacy and overcoming resistance.
  • This study provides a strong rationale for developing BET protein degraders as a novel treatment for brain cancers.
Keywords:
BRD2BRD3BRD4E2Fglioma

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