BRD4 Promotes Gastric Cancer Progression and Metastasis Through Acetylation-Dependent Stabilization of Snail

Cancer Res. 2019 Oct 1;79(19):4869-4881. doi: 10.1158/0008-5472.CAN-19-0442. Epub 2019 Jul 16.

Abstract

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. The abundance of BRD4 in human gastric cancer tissues correlated with shortened metastasis-free gastric cancer 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 of its putative transcriptional targets such as MYC or BCL2, but rather through stabilization of Snail at posttranslational levels. In an acetylation-dependent manner, BRD4 recognized acetylated lysine 146 (K146) and K187 on Snail to prevent Snail recognition by its E3 ubiquitin ligases FBXL14 and β-Trcp1, thereby inhibiting Snail polyubiquitination and proteasomal degradation. Accordingly, genome-wide transcriptome analyses identified that BRD4 and Snail regulate a partially shared metastatic gene signature in gastric cancer cells. These findings reveal a noncanonical posttranscriptional regulatory function of BRD4 in maintaining cancer growth and dissemination, with immediate translational implications for treating gastric metastatic malignancies with clinically available bromodomain inhibitors. SIGNIFICANCE: These findings reveal a novel posttranscriptional regulatory function of the epigenetic reader BRD4 in cancer metastasis via stabilizing Snail, with immediate translational implication for treating metastatic malignancies with clinically available bromodomain inhibitors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4869/F1.large.jpg.

MeSH terms

  • Acetylation
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Disease Progression
  • Epigenesis, Genetic / physiology
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Mice
  • Neoplasm Invasiveness / pathology*
  • Snail Family Transcription Factors / metabolism*
  • Stomach Neoplasms / pathology*
  • Transcription Factors / metabolism*
  • Transcriptome

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors