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Assays for Validating Histone Acetyltransferase Inhibitors
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Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP

Beth E Zucconi1,2, Jessica L Makofske1,3, David J Meyers4

  • 1Division of Genetics, Department of Medicine , Brigham and Women's Hospital , Boston , Massachusetts 02115 , United States.

Biochemistry
|March 30, 2019
PubMed

Insights

Combining two small molecules, A-485 and I-CBP112, effectively inhibits prostate cancer cell proliferation by reducing p300/CBP epigenetic enzyme occupancy on chromatin.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • p300 and CBP are related histone acetyltransferase (HAT) enzymes crucial for gene regulation.
  • Dysregulation of p300/CBP is implicated in various diseases, including cancer.
  • p300/CBP possesses a HAT domain inhibited by A-485 and a bromodomain antagonized by I-CBP112.

Purpose of the Study:

  • To investigate the synergistic effect of simultaneously inhibiting the HAT and bromodomain of p300/CBP.
  • To determine the impact of combined inhibition on prostate cancer cell proliferation and gene expression.
  • To analyze the effect of dual-domain inhibition on p300 chromatin occupancy.

Main Methods:

  • Utilized small molecules A-485 (HAT inhibitor) and I-CBP112 (bromodomain antagonist).
  • Assessed the combined effect on prostate cancer cell proliferation.
  • Quantified p300 chromatin occupancy using molecular techniques.
  • Measured mRNA levels of specific genes, including androgen-dependent and oncogenic targets.

Main Results:

  • The combination of I-CBP112 and A-485 synergistically inhibited prostate cancer cell proliferation.
  • Dual-domain inhibition led to a significant reduction in p300 chromatin occupancy compared to single-agent treatment.
  • Combination therapy reduced mRNA levels of key prostate cancer genes like KLK3 (PSA) and c-Myc.
  • Reduced mRNA levels correlated with decreased p300 occupancy at gene promoters.

Conclusions:

  • Concurrent targeting of the HAT and bromodomain of p300/CBP offers a pharmacologic advantage in inhibiting prostate cancer.
  • This dual-inhibition strategy effectively reduces cancer cell proliferation by altering p300 chromatin binding and gene expression.
  • Targeting key epigenetic regulators like p300/CBP presents a promising avenue for cancer therapy.

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