Zhang Qi, Han Zhenzhen, Liu Jia-Hui, Li Munan, Li Wei, Zhou Xin, Liu Xuelian
Cancer Center, The First Hospital of Jilin University, Changchun, China; Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Cancer Center, The First Hospital of Jilin University, Changchun, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Nov;1871(8):167993. doi: 10.1016/j.bbadis.2025.167993. Epub 2025 Jul 25.
The hypoxic tumor microenvironment, a hallmark of advanced solid tumors, is strongly associated with poor prognosis and reduced survival in colon cancer patients. Emerging evidence indicates that hypoxia serves as a key driver of cancer stemness by promoting the formation and maintenance of cancer stem cells (CSCs). However, the precise molecular mechanisms through which hypoxia induces CSC formation remain incompletely understood, particularly regarding the metabolic-epigenetic regulation of stemness characteristics. This study uncovers histone lactylation as a pivotal metabolic-epigenetic switch linking hypoxic stress to stemness in colorectal cancer cells. We demonstrate that hypoxia activates the HIF-1α/LDHA axis, driving lactate accumulation and triggering global histone lactylation (particularly H3K18la) in HT29 and SW480 cells. Crucially, lactylated histones directly bind and activate stemness gene promoters (OCT4/CD44/c-MYC), correlating with enhanced tumorsphere formation. Mechanistic validation through CRISPR-dCas9-HDAC3-mediated promoter-specific delactylation impaired stemness gene expression, demonstrating lactylation as a causal regulator. Our findings establish histone lactylation as a critical epigenetic regulator of hypoxia-induced stemness in colon cancer, revealing both its fundamental biological role and therapeutic potential. Targeting this lactylation-dependent pathway may disrupt CSC formation and enhance treatment efficacy.
缺氧肿瘤微环境是晚期实体瘤的一个标志，与结肠癌患者的不良预后和生存率降低密切相关。新出现的证据表明，缺氧通过促进癌症干细胞（CSCs）的形成和维持，成为癌症干性的关键驱动因素。然而，缺氧诱导CSC形成的确切分子机制仍未完全了解，特别是关于干性特征的代谢-表观遗传调控。本研究揭示组蛋白乳酸化是连接缺氧应激与结肠癌细胞干性的关键代谢-表观遗传开关。我们证明缺氧激活HIF-1α/LDHA轴，驱动乳酸积累并触发HT29和SW480细胞中的整体组蛋白乳酸化（特别是H3K18la）。至关重要的是，乳酸化组蛋白直接结合并激活干性基因启动子（OCT4/CD44/c-MYC），这与增强的肿瘤球形成相关。通过CRISPR-dCas9-HDAC3介导的启动子特异性去乳酸化进行的机制验证损害了干性基因表达，证明乳酸化为因果调节因子。我们的研究结果确立了组蛋白乳酸化是结肠癌缺氧诱导干性的关键表观遗传调节因子，揭示了其基本生物学作用和治疗潜力。靶向这种依赖乳酸化的途径可能会破坏CSC的形成并提高治疗效果。
