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Chemical Perturbations Impacting Histone Acetylation Govern Colorectal Cancer Differentiation
Pornlada Likasitwatanakul1, Zhixin Li2, Paul Doan3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts; Department of Medicine, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand.
Background & Aims:
Aberrant epigenetic programs that suppress differentiation and enhance plasticity drive colorectal cancer (CRC), yet the molecular determinants underlying these processes remain elusive. We aimed to identify and characterize epigenetic regulators of CRC differentiation, uncovering mechanisms that reprogram cancer cell states.
Methods:
A small-molecule library targeting epigenetic regulators was screened using an endogenous dual-reporter system. We evaluated lead compounds in mouse and human CRC models via histopathology, cellular assays, epigenetic studies, mass spectrometry-based histone modification profiling, and single-cell RNA sequencing. Integrative analyses of drug-induced chromatin dynamics, gene expression, target engagement, and histone marks elucidated molecular mechanisms. Focused genetic screens were conducted to identify regulators of histone deacetylase (HDAC)1/2-mediated differentiation.
Results:
We found that inhibition of the HDAC1/2 catalytic domain promotes CRC differentiation and suppresses tumor growth. Unbiased profiling of histone modifications identified acetylation of lysine 27 on histone H3 protein subunit (H3K27ac) and acetylation of lysine 9 on histone H3 protein subunit (H3K9ac) as critical regulatory marks, with genome-wide analyses demonstrating their enrichment at HDAC1/2-bound regions associated with open chromatin and up-regulated differentiation genes. Disrupting H3K27ac by targeted degradation of acetyltransferase E1A binding protein P300 reversed the differentiation phenotype induced by HDAC1/2 inhibition in a patient-derived CRC organoid. Genetic screens revealed that death-associated protein kinase 3 contributes to H3K27ac-mediated CRC differentiation induced by HDAC1/2 inhibition.
Conclusions:
Our findings establish histone acetylation as a chemically targetable mechanism governing CRC cell fate and demonstrate that epigenetic reprogramming can be leveraged as a therapeutic strategy. By identifying HDAC1/2 inhibition as a driver of differentiation and revealing H3K27ac as a key regulatory mark, this study provides a framework for targeting chromatin-modifying enzymes to counteract CRC plasticity and improve treatment outcomes.
Insights
Targeting histone deacetylase (HDAC)1/2 promotes colorectal cancer (CRC) differentiation and suppresses tumor growth. Histone acetylation, particularly H3K27ac, is a key epigenetic mechanism for reprogramming CRC cell states and offers a therapeutic strategy.
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.
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