BRD4 promotes gastric cancer progression and metastasis through acetylation-dependent stabilization of Snail

Cancer metastasis, a leading cause of death in patients, is associated with aberrant expression of epigenetic modifiers, yet it remains poorly defined how epigenetic readers drive metastatic growth and whether epigenetic readers are targetable to control metastasis. Here, we report that Bromodomain-containing protein 4 (BRD4), a histone acetylation reader and emerging anticancer therapeutic target, promotes progression and metastasis of gastric cancer (GC). The abundance of BRD4 in human GC tumor tissues correlated with shortened metastasis-free GC patient survival. Consistently, BRD4 maintained invasiveness of cancer cells in vitro and their dissemination at distal organs in vivo. Surprisingly, BRD4 function in this context was independent on its putative transcriptional targets such as MYC or BCL2, but rather through stabilization of Snail at post-translational levels. In an acetylation-dependent manner, BRD4 recognized acetylated lysine 146 (K146) and K187 on Snail to exclude Snail recognition by its E3 ubiquitin ligases FBXL14 and β-Trcp1, thereby inhibiting Snail polyubiquitination and proteasomal degradation. Accordingly, genome-wide transcriptome analysis identified that BRD4 and Snail regulate a partially shared metastatic gene signature in GC cells. These findings reveal a non-canonical post-transcriptional regulatory function of BRD4 in maintaining cancer growth and dissemination, with immediate translational implication for treating gastric metastatic malignancies with clinically available bromodomain inhibitors.