Butyrate blocks cell cycle progression in colorectal cancer organoids partially through HDAC2 inhibition

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Introduction: Butyric acid is a major gut microbiota metabolite that exhibits many biological functions, including the suppression of colorectal cancer (CRC) growth. However, previous studies have mainly been conducted using cell lines, which do not recapitulate the genuine three-dimensional spatial characteristics of CRC. In this study, we explored the therapeutic outcome and precise molecular targets of butyrate with sodium butyrate (NaB) using tumor organoids of CRC. Methods: Firstly, we examined the influence of butyrate on CRC subcutaneous allografts. And then the biological effects of butyrate were mainly determined using CRC organoids derived from KPC mice and Caco-2 cells. The morphological characteristics of butyrate-treated CRC organoids were analyzed, and multiple experimental assays were employed to determine the biological and molecular influences of butyrate. Finally, the inhibitor of HDAC2 was used to mimic the biological effects of butyrate on CRC organoids. Results: It was observed that butyrate significantly suppressed the growth of CRC allografts. Importantly, butyrate could apparently inhibit the proliferation, disrupt epithelial integrity, and induce apoptosis in CRC organoids. Transcriptomic analyses revealed that butyrate acts as an epigenetic modulator, targeting HDAC2 and selectively repressing its transcription. This led to inhibition of cyclin D1, CDK4/6, and upregulation of p21 expression, suggesting cell cycle arrest. The selective HDAC2 inhibitor similarly recapitulated the influences of butyrate on CRC organoids. Discussion: Butyrate exerts the definitive blocking effects on cell cycle progression in CRC organoids, and HDAC2 is one of the important targets. Butyrate modulates cell cycle via targeting HDAC2, constituting a novel therapeutic pathway for CRC. This study provides new evidence for gut microbial metabolites as a potential means for the prevention and treatment of colorectal cancer.

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