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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers

Published on: September 20, 2018

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Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk

Sara Sdelci1, Charles-Hugues Lardeau1,2, Cynthia Tallant3,4

  • 1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Nature Chemical Biology
|May 10, 2016
PubMed

Insights

Researchers screened compounds to find new cancer therapies. They discovered that TAF1, a protein, works with BRD4 to control cancer cell growth, making it a potential new target for treating MYC-driven cancers.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Chemical Biology

Background:

  • Bromodomain and Extra-Terminal domain (BET) proteins regulate gene transcription via histone acetylation.
  • BET inhibitors show therapeutic potential in various cancers, including those driven by the MYC oncogene.
  • BRD4 is a key BET protein involved in regulating heterochromatin and gene expression.

Purpose of the Study:

  • To identify novel small molecules that modulate BRD4 function using a high-diversity chemical screen.
  • To investigate compounds that mimic BRD4 inhibition without direct engagement.
  • To explore the role of TAF1 in cancer cell proliferation and its potential as an epigenetic target.

Main Methods:

  • High-diversity chemical compound screening in human cells.
  • Assay development for monitoring BRD4-dependent heterochromatization.
  • Pharmacological inhibition of TAF1's second bromodomain.
  • Analysis of cancer cell proliferation and gene expression.

Main Results:

  • Identified known and novel compounds targeting BRD4.
  • Discovered small molecules that inhibit TAF1, mimicking BRD4 inhibition.
  • Demonstrated that TAF1 synergizes with BRD4 to control cancer cell proliferation.
  • Established TAF1 as a potential therapeutic target in MYC-driven cancers.

Conclusions:

  • TAF1 plays a critical role in cancer cell proliferation by cooperating with BRD4.
  • TAF1 inhibition represents a promising epigenetic strategy for treating MYC-driven cancers.
  • The identified TAF1 inhibitor provides a tool for further research into epigenetic regulation in cancer.

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