| Summary: | Bromodomain and extra-terminal (BETs) proteins function as epigenetic readers by docking onto acetylated lysine residues (Kac) on histone tails via tandem bromodomains (BRDs), and recruiting protein binding partners via an extra-terminal recruitment domain (ET). Targeting BET BRDs is efficacious in different malignancy models; however, the underlying mechanisms remain largely unknown in solid tumours. Together with concerns over toxicity, this calls for a greater understanding of BET protein biology and alternative targeting approaches. p53 influences the phenotype observed in haematopoietic cells following BET BRD inhibition, so it was investigated whether p53 has a similar regulatory role in melanoma. Here, I show that melanoma cells undergo senescence or apoptosis following BET BRD inhibition, and that p53 mutation status potentially correlates with this cell fate decision. Furthermore, BET inhibition up-regulates autophagic flux in melanoma and prostate cancer cells. However, the effect of concomitant autophagy inhibition on cellular proliferation is heterogeneous. Finally, ET domain inhibition leads to autophagy- dependent senescence in melanoma, which provides proof-of-principle that both Kac- dependent and independent targeting of BETs yield a loss of cell viability.
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