Ji Yang, Xu Zhenggang, Tang Lei, Huang Tianyu, Mu Xiaoxin, Ni Chuangye, Tang Bai, Lu Hao, Zhang Chuanyong, Yang Shikun, Wang Xuehao
Medical College, Yangzhou University, Yangzhou, China; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China.
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China.
Cancer Lett. 2025 Oct 28;631:217957. doi: 10.1016/j.canlet.2025.217957. Epub 2025 Jul 26.
Metabolic reprogramming is a hallmark of tumorigenesis and progression, with alterations in glucose metabolism, often referred to as the Warburg effect, playing a central role. This shift allows tumor cells to rapidly acquire energy and generate essential metabolic intermediates, thereby supporting enhanced growth. Despite its significance, the mechanisms by which tumor cells upregulate glycolysis remain inadequately understood. In this study, we report that YBX1 is highly expressed in hepatocellular carcinoma (HCC) and is closely associated with glycolysis. We show that YBX1 is modified by O-linked N-acetylglucosamine (O-GlcNAc) at threonine 57 (T57), which stabilizes the protein and increases its expression. This modification also promotes the phosphorylation of YBX1 at serine 102, facilitating its nuclear translocation. Consequently, this process enhances the transcription of glycolysis-related genes and stimulates lactate production. Moreover, YBX1 activates the transcription of P300, which in turn drives the lactylation of histones, particularly H3K18la. Cleavage Under Targets and Tagmentation (CUT&Tag) analysis reveals that H3K18 lactylation positively regulates YBX1 gene transcription. Our findings establish a positive feedback loop involving YBX1, glycolysis, and H3K18 lactylation that accelerates HCC progression. Disrupting this feedback loop may provide a novel therapeutic strategy for HCC.
代谢重编程是肿瘤发生和进展的一个标志，其中葡萄糖代谢的改变（通常称为瓦伯格效应）起着核心作用。这种转变使肿瘤细胞能够快速获取能量并产生必需的代谢中间体，从而支持其加速生长。尽管其具有重要意义，但肿瘤细胞上调糖酵解的机制仍未得到充分理解。在本研究中，我们报告YBX1在肝细胞癌（HCC）中高表达，并且与糖酵解密切相关。我们发现YBX1在苏氨酸57（T57）处被O-连接的N-乙酰葡糖胺（O-GlcNAc）修饰，这使该蛋白稳定并增加其表达。这种修饰还促进YBX1在丝氨酸102处的磷酸化，促进其核转位。因此，这一过程增强了糖酵解相关基因的转录并刺激乳酸生成。此外，YBX1激活P300的转录，进而驱动组蛋白的乳酰化，特别是H3K18la。靶向切割与标记（CUT&Tag）分析表明，H3K18乳酰化正向调节YBX1基因转录。我们的研究结果建立了一个涉及YBX1、糖酵解和H3K18乳酰化的正反馈回路，该回路加速了HCC的进展。破坏这个反馈回路可能为HCC提供一种新的治疗策略。
