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Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation

Pornlada Likasitwatanakul1,2,3,4, Zhixin Li1,2,3, Paul Doan1,3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Biorxiv : the Preprint Server for Biology
|December 23, 2024
PubMed

Insights

Inhibiting histone deacetylase (HDAC) 1/2 promotes colorectal cancer (CRC) differentiation and anti-tumor activity by altering histone acetylation. This epigenetic reprogramming highlights a potential therapeutic strategy for CRC.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Dysregulated epigenetic programs are critical to colorectal cancer (CRC) development, promoting uncontrolled cell growth and plasticity.
  • Histone deacetylases (HDACs) play a key role in regulating gene expression and cellular differentiation.
  • Targeting epigenetic regulators offers a promising avenue for novel CRC therapies.

Purpose of the Study:

  • To investigate the role of histone deacetylase 1/2 (HDAC1/2) inhibition in promoting colorectal cancer differentiation.
  • To elucidate the epigenetic mechanisms underlying HDAC1/2 inhibition-induced anti-tumor activity.
  • To identify potential therapeutic strategies for colorectal cancer based on epigenetic reprogramming.

Main Methods:

  • Screening of a small molecule library targeting epigenetic regulators using a dual reporter system.
  • Biochemical, chemical, and genetic experiments to analyze HDAC1/2 function and inhibition.
  • Profiling of histone posttranslational modifications and genome-wide assessment of histone marks (e.g., H3K27ac).
  • Single-cell RNA-sequencing and genetic screens to identify contributing factors like EP300 and DAPK3.

Main Results:

  • Inhibition of HDAC1/2 promotes colorectal cancer differentiation and anti-tumor activity through blockade of the catalytic domain.
  • HDAC1/2 inhibition leads to increased H3K27ac at specific genomic regions, associated with open chromatin and differentiation gene upregulation.
  • Degradation of EP300 rescues HDAC1/2 inhibitor-mediated differentiation, and DAPK3 contributes to this process.
  • Specific histone modifications are crucial in governing cancer cell states.

Conclusions:

  • HDAC1/2 inhibition represents a viable therapeutic strategy for colorectal cancer by inducing differentiation.
  • Targeting specific histone modifications, such as H3K27ac, is key to epigenetic reprogramming in CRC.
  • Understanding the interplay between epigenetic regulators and histone modifications can lead to novel cancer treatments.
Keywords:
colorectal cancerepigenetic regulationintestinal differentiationstem cell

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