β-hydroxybutyrate resensitizes colorectal cancer cells to oxaliplatin by suppressing H3K79 methylation in vitro and in vivo
Background: Ketone β-hydroxybutyrate (BHB) has been shown to inhibit tumor cell proliferation and enhance drug sensitivity. However, its potential to overcome oxaliplatin (Oxa) resistance in colorectal cancer (CRC) and the mechanisms involved remain unclear.
Methods: CRC-Oxa-resistant cell lines were developed by exposing CRC cells to incrementally increasing concentrations of Oxa. The effects of BHB on CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were evaluated in vitro. In vivo, subcutaneous and metastatic tumor models were used to investigate the impact of BHB on CRC-Oxa growth and metastasis. The study also included eight Oxa-responsive and seven Oxa-resistant CRC patients to assess serum BHB levels and the expression of histone modifications (H3K79me, H3K27ac, H3K14ac, and H3K9me) in tissue samples. Further analysis was performed using DOT1L (H3K79 methyltransferase) knockdown and the H3K27ac inhibitor GNE-049 to determine whether BHB reversed Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vitro and in vivo.
Results: BHB treatment in combination with Oxa suppressed CRC-Oxa cell proliferation, migration, invasion, and EMT in vitro, as well as tumor growth and metastasis in mouse models. Clinical analysis showed that serum BHB levels were significantly lower in Oxa-resistant patients and correlated with resistance. Additionally, the expression of H3K79me, H3K27ac, and H3K14ac in CRC tissues was inversely correlated with BHB levels. Mechanistic studies revealed that inhibition of H3K79 methylation disrupted BHB’s ability to restore drug sensitivity, highlighting its importance in mediating the observed effects.
Conclusions: β-hydroxybutyrate restores sensitivity to oxaliplatin in CRC by suppressing H3K79 methylation in both in vitro and in vivo models.