Colorectal cancer (CRC) arises from genetic and epigenetic alterations, including histone modifications. Unlike genetic changes, epigenetic alterations are reversible, making them attractive therapeutic targets. This review focuses on histone acetylation, methylation, and phosphorylation dysregulated in CRC, and evaluates natural and synthetic epigenetic modifiers targeting these alterations.
Histone Modifications in CRC
Acetylation: Global H3 acetylation is increased (poor prognosis); H4K12ac, H3K9ac, H3K18ac, H3K56ac, and H4K16ac are decreased (associated with progression).
Methylation: H3K9me3, H3K4me2, H3K27me3, and H3K79me2 are increased; H3K4me3, H3K36me2, and H4K20me3 are decreased.
Phosphorylation: H3S10ph (by Aurora B) and γ-H2AX are increased, involved in proliferation and DNA damage.
Epigenetic Modifiers Targeting Histone Acetylation
Key HDAC inhibitors (HDACis) in CRC include:
Vorinostat, Belinostat, Resminostat: Hydroxamic acid HDACis; enhance chemotherapy sensitivity; belinostat's copper complex (Cubisbel) improved stability and efficacy.
Valproic Acid: Class I HDACi; induces apoptosis and cell cycle arrest.
Psammaplin A, Parthenolide, Trichostatin A: Natural products with HDAC inhibitory activity; upregulate tumor suppressors and induce apoptosis.
Other hydroxamates (MHY218, WMJ-S-001): Induce p53 activation and suppress xenograft growth.
Epigenetic Modifiers Targeting Histone Methylation
Key histone methyltransferase inhibitors:
Ribavirin: PRMT5 inhibitor; reduces H3R8me2s and H4R3me2s; suppresses CRC growth.
Pinometostat: DOT1L inhibitor; synergistic with 5-FU.
UNC0638: G9a/GLP inhibitor; enhances topoisomerase inhibitor cytotoxicity.
Verticillin A: Inhibits multiple HMTs; restores FAS expression and overcomes 5-FU resistance.
3-Deazaneplanocin A, GSK343, GSK126: EZH2 inhibitors; reduce H3K27me3, suppress tumor growth, and modulate immunity.
Epigenetic Modifiers Targeting Histone Phosphorylation
Barasertib: Aurora B inhibitor; suppresses cyclin E1 and sensitizes to 5-FU.
Alisertib: Aurora A inhibitor; induces apoptosis and autophagy; synergistic with MEK inhibitors.
Staurosporine, Lestaurtinib: Broad kinase inhibitors; block mitotic histone phosphorylation and induce apoptosis.
WMJ-S-001: Hydroxamate derivative; induces p53 phosphorylation and suppresses xenograft growth.
Limitations and Future Challenges
Current epidrugs face off-target effects, toxicity, and resistance. Emerging strategies include:
Combination therapies: HDACis with chemotherapy, immunotherapy, or radiotherapy.
Epigenetic degraders: PROTACs (e.g., dBET1, MS1943) and molecular glues offer targeted protein degradation; in CRC, PROTACs targeting KDM3A/B eliminate cancer stem cells via Wnt/β-catenin inhibition.
Expanding targets: Ubiquitination, sumoylation, ADP-ribosylation, and neddylation remain underexplored.
Conclusions
Epigenetic modifiers targeting histone acetylation, methylation, and phosphorylation show significant preclinical promise in CRC. Combination strategies and novel degraders offer pathways to overcome resistance. Future research should focus on clinical translation, target expansion, and optimized combination regimens to improve outcomes for CRC patients.
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The study was recently published in the Gene Expression .
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