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Updated: Jun 20, 2025

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
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Chromatin assembly factor 1 suppresses epigenetic reprogramming toward adaptive drug resistance

Zhiquan Wang1, Rentian Wu1, Qian Nie1

  • 1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.

Journal of the National Cancer Center
|July 22, 2024
PubMed

Insights

Targeted cancer therapy resistance in melanoma involves epigenetic changes. Restoring histone H3 lysine 9 trimethylation (H3K9me3) may overcome resistance to BRAF inhibitors by targeting chromatin assembly factor 1 (CAF-1).

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Targeted cancer therapies, like BRAF inhibitors (BRAFi), face challenges due to acquired resistance.
  • Epigenetic reprogramming is implicated in resistance, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the role of epigenetic modifications in adaptive BRAF inhibitor resistance in melanoma.
  • To identify specific molecular mechanisms contributing to BRAFi resistance.

Main Methods:

  • Analysis of chromatin accessibility changes in melanoma cells developing adaptive BRAFi resistance.
  • Assessment of chromatin assembly factor 1 (CAF-1) and histone H3 lysine 9 trimethylation (H3K9me3) levels.
  • Investigating the impact of CAF-1 depletion on chromatin plasticity and AP1 component reprogramming.

Main Results:

  • Increased chromatin accessibility was observed in adaptive BRAFi-resistant melanoma cells.
  • Loss of CAF-1 and associated H3K9me3 marks correlated with acquired BRAFi resistance.
  • CAF-1 depletion facilitated chromatin plasticity, enabling AP1 component reprogramming and promoting BRAFi resistance.

Conclusions:

  • Adaptive BRAF inhibitor resistance in melanoma is linked to increased chromatin accessibility and loss of CAF-1/H3K9me3.
  • Therapeutic strategies aimed at restoring H3K9me3 levels could potentially overcome CAF-1 loss and suppress BRAFi resistance.
Keywords:
Adaptive drug resistanceBRAF inhibitorChromatin assembly factor 1Epigenetic reprogrammingH3K9me3Nucleosome assemblyTargeted therapy

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