BET BROMODOMAIN INHIBITORS AFFECT REPLICATION & CELL CYCLE PROGRESSION

Myc family transcription factors contribute to pathogenesis in most cancers and their expression projects a poor prognosis (1). Genetic and pharmacological inhibition of Myc and several Myc targets leads to apoptosis and tumor regression. Recently, inhibitors of BET Bromodomain proteins (BETi) were shown to have anti-tumor properties and this has been attributed to Myc down-regulation (2). In this study, we show that two structurally distinct BETi affect replication and cell cycle progression at low concentrations where the transcriptome remains largely unaltered. At these concentrations, S-phase progression is hindered, as assessed by thymidine incorporation and flow cytometry analyses. However, in a cell-free system replication is not impaired suggesting that BETi-mediated block of replication is linked to effects on chromatin. Furthermore, at higher concentration of BETi, S-phase entry of cells is completely abrogated. Ectopic expression of Myc fails to rescue these phenotypes, suggesting a novel function of BET bromodomain proteins in replication and cell cycle regulation.