EGR1 induction compromises the therapeutic efficacy of BET depletion in triple-negative breast cancer (ChIP-Seq)

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers of acetylated lysine residues, which regulate gene expression and are involved in tumorigenesis. Over the past two decades, BET-bromodomain (BD) inhibitors and BET-targeting PROTAC degraders have been developed and clinically tested. BET protein depletion with PROTAC degrader is generally recognized to provide stronger outcomes compared to just inhibiting the binding of protein to acetylated lysine residues with competitive inhibitors. In this study, we found that the bivalent BET-BD inhibitor MS645 exhibited much more potent anti-proliferative activity than BET degraders, including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer cells. MS645 treatment dissociated BET proteins from chromatin and decreased E2F1-3 expression, thus inhibited cell growth of TNBC. While ARV771 treatment didn't affect E2F1-3 expression though it displaced BET proteins from chromatin as well. We found knockdown of BRD4 or BRD4 depletion by ARV771 treatment dramatically induced EGR1 expression. EGR1 interacts with Septin complex and maintained its nuclear distribution. Septin complex is recruited by EGR1 to E2F1-3 gene loci to activate E2F1-3 transcription, thus maintained cell cycle progression. Overall design: To investigate the genomic occupancy of BRD4, H3K27ac and EGR1 upon MS645 and ARV771 treatment, HCC1806 cells were treated with different chemicals and ChIP-seq was performed