BRD4

Overview

BRD4 is a member of the BET (bromodomain and extraterminal domain) family of chromatin readers, recognizing acetylated lysine residues on histone tails to regulate transcriptional elongation. BRD4 is a well-established oncogenic dependency in multiple cancer types, particularly those driven by MYC amplification or SWI/SNF complex loss. JQ1, a small-molecule BET inhibitor, competitively displaces BRD4 from chromatin and suppresses oncogenic transcription programs.

Alterations observed in the corpus

  • BRD4-binding sites increase at chromatin loci in ARID1A-knockout SCLC cells, establishing BRD4 occupancy as an adaptive response to SWI/SNF complex loss and the mechanistic basis for enhanced JQ1 sensitivity PMID:22037554
  • BRD4–NUTM1 fusion present in the TY82 thymic carcinoma cell line PMID:24974848
  • BET bromodomain protein occupying super-enhancers at MYB locus and other MYB target genes in adenoid cystic carcinoma (ACC); grade-2 ACC shows functional dependency on BRD4/BET activity, and BET inhibitor JQ1 suppresses tumour growth in ACC primagraft models PMID:26829750
  • BRD4 involved in a novel NUTM1-BRD4 in-frame fusion (NUT exons 1-2, BRD4 exons 14-20) in a single ATC case from a 34-year-old woman who was alive 10 years post-diagnosis — a clinical outlier in the PDTC/ATC cohort (n=117) PMID:26878173
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Cancer types (linked)

  • SCLC: BRD4 is a therapeutic target in ARID1A-low/deficient SCLC; JQ1 IC50 values correlate inversely with ARID1A expression (r = 0.368, P = 0.032) in SCLC cell lines (GDSC1 dataset) PMID:22037554

Co-occurrence and mutual exclusivity

  • BRD4 dependency is enhanced in tumors with loss of ARID1A (SWI/SNF complex); ARID1A depletion increases BRD4 chromatin binding and sensitizes cells to JQ1 PMID:22037554
  • BRD4 inhibition by JQ1 suppresses MYC transcription and downregulates RAD51 and phospho-CHEK1, implicating the BRD4-MYC axis in DNA damage response PMID:22037554

Therapeutic relevance

  • JQ1 (BET bromodomain inhibitor) shows selective antitumor activity in ARID1A-low SCLC cell lines and xenografts; combination with BRD-K98645985 (BAF complex inhibitor) achieves Bliss synergy and superior tumor suppression vs. either agent alone (P < 0.0001) PMID:22037554

Open questions

  • JQ1 is a tool compound; clinical BET inhibitors (e.g., molibresib, birabresib) have not been tested in ARID1A-stratified SCLC populations.
  • The generalizability of BRD4 synthetic lethality with ARID1A loss across SCLC molecular subtypes (ASCL1, NEUROD1, POU2F3, YAP1) remains uncharacterized.

Sources

  • PMID:22037554 — ARID1A Governs Genomic Stability and Proliferation in SCLC via c-MYC/PARP1 Suppression Driving Vulnerability to BET Inhibitors

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