Regulation of the transcription cycle contributes to BET bromodomain inhibitor resistance [RNA-seq]

Bromodomain (BRD)-containing proteins, multi-domain scaffolding molecules implicated in the relay of acetylated lysine (Kac) signals, are tractable targets for cancer therapeutics. However, their functions and the consequences of targeting them have not been systematically characterized. Employing complementary interaction-mapping techniques (affinity purification and proximity-dependent biotinylation), we investigate the interactome of 39 BRD-containing proteins together with 110 additional proteins that physically or functionally associate with them. We uncover 4096 novel interactions, revealing intricate connectivity of the Kac-machinery. We survey interaction landscape rewiring following chemical inhibition for multiple class of BRDs and revealed highly distinctive response following pharmacological intervention between BRD-containing proteins families. Lastly, focusing on the BET protein family, we characterized their interplay with the p38/MAPKAPK2 stress signaling pathway and its contribution to metabolic alterations in the context of metastatic cutaneous melanoma.