Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Baicalein specifically suppresses microsatellite instability colorectal cancer by targeting adenosylhomocysteinase to inhibit histone H3 lysine 4 trimethylation-mediated cancer stemness.
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Zheng Yaqiu, Li Yu, Lu Minling, Jia Zhen, Wan Ting, Li Zizheng, Huang Yukai, Zhou Chishun, Zeng Huiyan, Jin Xin, Liu Zhongqiu, Lu Linlin
Аннотация
BACKGROUND: Patients with microsatellite instability (MSI) colorectal cancer (CRC) face significant challenges due to chemotherapy resistance and limited immunotherapy response, underscoring the urgent need for MSI-specific therapies. Baicalein, a trihydroxyflavone compound derived from Scutellaria baicalensis, has demonstrated tumor-suppressive potential. However, its efficacy and mechanism in MSI CRC remain unexplored.
PURPOSE: This study investigates the therapeutic effects of baicalein on MSI CRC and elucidates the potential molecular mechanisms underlying its tumor-specific effects.
METHODS: We assessed baicalein's efficacy using cell-derived xenograft models and multiple CRC cell lines. Mechanistic studies employed Sepharose 4B-conjugated baicalin affinity purification to identify binding targets. Multiple biochemical assays were performed to further characterize the binding affinity of baicalein to the target protein. Histone methylation levels and stemness gene expression were analyzed by Western blot. Finally, the relevance of baicalein's target and associated pathway in MSI CRC was validated using clinical patient tissues and patient-derived xenograft (PDX) models.
RESULTS: Baicalein exhibited superior efficacy against MSI CRC compared to microsatellite stable (MSS) CRC in both in vivo and in vitro models. Mechanistically, adenosylhomocysteinase (AHCY) was identified as a key direct target of baicalein. In MSI CRC cells, AHCY forms more hyperactive tetramers, baicalein binds to AHCY at residues D134 and D303, and disrupts tetramer formation and enzymatic activity. This inhibition triggered S-adenosylhomocysteine (SAH) accumulation, decreased histone H3 lysine 4 trimethylation (H3K4me3), and downregulated stemness markers OCT4 and Nanog. Critically, we observed constitutive activation of the AHCY/H3K4me3 axis in MSI tissues and cells, while baicalein treatment effectively suppressed AHCY activity and attenuated H3K4me3-mediated cancer stemness in MSI PDX models.
CONCLUSIONS: This was the first study to confirm the differential efficacies of baicalein on MSI versus MSS CRC and to identify AHCY as a novel therapeutic target for MSI CRC. Baicalein directly targets AHCY, suppressing H3K4me3-mediated cancer stemness, and represents a promising targeted therapy for MSI CRC.
PURPOSE: This study investigates the therapeutic effects of baicalein on MSI CRC and elucidates the potential molecular mechanisms underlying its tumor-specific effects.
METHODS: We assessed baicalein's efficacy using cell-derived xenograft models and multiple CRC cell lines. Mechanistic studies employed Sepharose 4B-conjugated baicalin affinity purification to identify binding targets. Multiple biochemical assays were performed to further characterize the binding affinity of baicalein to the target protein. Histone methylation levels and stemness gene expression were analyzed by Western blot. Finally, the relevance of baicalein's target and associated pathway in MSI CRC was validated using clinical patient tissues and patient-derived xenograft (PDX) models.
RESULTS: Baicalein exhibited superior efficacy against MSI CRC compared to microsatellite stable (MSS) CRC in both in vivo and in vitro models. Mechanistically, adenosylhomocysteinase (AHCY) was identified as a key direct target of baicalein. In MSI CRC cells, AHCY forms more hyperactive tetramers, baicalein binds to AHCY at residues D134 and D303, and disrupts tetramer formation and enzymatic activity. This inhibition triggered S-adenosylhomocysteine (SAH) accumulation, decreased histone H3 lysine 4 trimethylation (H3K4me3), and downregulated stemness markers OCT4 and Nanog. Critically, we observed constitutive activation of the AHCY/H3K4me3 axis in MSI tissues and cells, while baicalein treatment effectively suppressed AHCY activity and attenuated H3K4me3-mediated cancer stemness in MSI PDX models.
CONCLUSIONS: This was the first study to confirm the differential efficacies of baicalein on MSI versus MSS CRC and to identify AHCY as a novel therapeutic target for MSI CRC. Baicalein directly targets AHCY, suppressing H3K4me3-mediated cancer stemness, and represents a promising targeted therapy for MSI CRC.