BET bromodomain is a novel regulator of TAZ and its activity

Biochim Biophys Acta. 2016 Dec;1859(12):1527-1537. doi: 10.1016/j.bbagrm.2016.10.001. Epub 2016 Oct 4.

Abstract

Transcriptional coactivator with PDZ-binding motif (TAZ) is a key transcriptional mediator of Hippo signaling that has been recently reported to mediate Wnt-activated transcription and serve as a component to suppress canonical Wnt/β-catenin activity. The Bromodomain and Extra-terminal domain (BET) family of proteins can recognize the acetylated lysine chain on histones and plays a critical role in transcriptional regulation. However, the mechanisms underlying transcriptional repression by the BET bromodomain are poorly understood. Here, we found that BET bromodomain inhibition upregulated TAZ protein and its transcriptional output, independent of its well-established role as a mediator of Hippo and Wnt signaling. Additionally, JQ1, a synthetic BET inhibitor, suppressed Wnt/β-catenin activity by upregulating TAZ. Although JQ1 upregulated TAZ, which is known to promote cell proliferation, it drastically suppressed the growth of colon cancer cells by inducing cell cycle arrest. Collectively, our study identified an unexpected transcriptional repression function of the BET bromodomain and a novel mechanism for TAZ upregulation.

Keywords: Bromodomain and extra-terminal domain protein (BET); Colon cancer; TAZ; β-Catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Checkpoints / genetics
  • Cell Proliferation / genetics
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic / genetics
  • HCT116 Cells
  • Humans
  • Mice
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics*
  • Proteins / genetics*
  • Signal Transduction
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*
  • Transcriptional Activation / genetics*
  • Wnt Signaling Pathway
  • Xenograft Model Antitumor Assays
  • beta Catenin / genetics

Substances

  • Nuclear Proteins
  • Proteins
  • TAZ protein, human
  • Transcription Factors
  • beta Catenin
  • bromodomain and extra-terminal domain protein, human