Chemical Perturbations Impacting Histone Acetylation Govern Colorectal Cancer Differentiation

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• Aberrant epigenetic programs drive colorectal cancer (CRC) by suppressing differentiation and enhancing plasticity.
• The molecular drivers of these CRC-associated epigenetic changes are not fully understood.
• Identifying epigenetic regulators is crucial for understanding and reprogramming cancer cell states.

Purpose of the Study:

• To identify and characterize epigenetic regulators of colorectal cancer (CRC) differentiation.
• To uncover mechanisms that reprogram cancer cell states in CRC.
• To explore therapeutic strategies targeting epigenetic pathways in CRC.

Main Methods:

• Screening of a small-molecule library targeting epigenetic regulators using a dual-reporter system.
• Evaluation of lead compounds in mouse and human CRC models using histopathology, cellular assays, and epigenetic studies.
• Single-cell RNA sequencing, mass spectrometry-based histone modification profiling, and genetic screens to elucidate molecular mechanisms.

Main Results:

• Inhibition of histone deacetylase (HDAC)1/2 catalytic domain promotes CRC differentiation and suppresses tumor growth.
• Histone modifications H3K27ac and H3K9ac were identified as critical regulatory marks enriched at HDAC1/2-bound regions.
• Targeted degradation of E1A binding protein P300 reversed HDAC1/2 inhibition-induced differentiation, and death-associated protein kinase 3 was implicated in H3K27ac-mediated differentiation.

Conclusions:

• Histone acetylation is a chemically targetable mechanism governing CRC cell fate.
• Epigenetic reprogramming via targeting chromatin-modifying enzymes can be a therapeutic strategy for CRC.
• HDAC1/2 inhibition and H3K27ac regulation provide a framework for counteracting CRC plasticity and improving treatment outcomes.