BET Inhibitors Induce p53-Independent Growth Arrest in HCT116 Cells via Epigenetic Control of the E2F1/c-MYC Axis

抄録

Although bromodomain and extraterminal (BET) inhibitors (BETis) have anti-tumor potential, the underlying molecular mechanism is poorly understood. We found that BETis effectively repressed cell growth via G1/S arrest and migration of HCT116 cells in a p53-independent manner. BETis increased the expression of p21WAF1 and repressed the expression of E2F target genes. Consistent with this, retinoblastoma protein (Rb) phosphorylation was downregulated by BETis, supporting E2F inactivation. To investigate the epigenetic mechanism, chromatin immunoprecipitation (ChIP) assays were employed using the E2F1 target gene c-MYC. Following BETi treatment, recruitment of phosphorylated Rb, BRD2, and MLL2 to the c-MYC promoter was reduced, whereas recruitment of unphosphorylated Rb and EZH2 was increased. Consequently, decreased H4K5/K12ac and H3K4me3 accumulation but increased H3K27me3 accumulation were observed. Overall, this study suggests that BETis may be useful for the treatment of colorectal cancer via epigenetic regulation of the E2F1/c-MYC axis, leading to growth arrest in a p53-independent manner.