Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29764999.
- Also identified by DOI 10.1073/pnas.1712363115 and PMC identifier 5984485.
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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.
Medical subject headings
- Antineoplastic Agents
- E2F1 Transcription Factor
- Glioblastoma
- Protein Serine-Threonine Kinases
- RNA-Binding Proteins