BRD4 inhibitor inhibits colorectal cancer growth and metastasis

Int J Mol Sci. 2015 Jan 16;16(1):1928-48. doi: 10.3390/ijms16011928.

Abstract

Post-translational modifications have been identified to be of great importance in cancers and lysine acetylation, which can attract the multifunctional transcription factor BRD4, has been identified as a potential therapeutic target. In this paper, we identify that BRD4 has an important role in colorectal cancer; and that its inhibition substantially wipes out tumor cells. Treatment with inhibitor MS417 potently affects cancer cells, although such effects were not always outright necrosis or apoptosis. We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT). This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro. Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Dibenzazepines / pharmacology*
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms / secondary*
  • Male
  • Mice, Nude
  • Middle Aged
  • Neoplasm Metastasis / drug therapy*
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Young Adult

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Dibenzazepines
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factors