Liu Zijian, Han Jiaqi, Su Shitong, Zeng Qiwen, Wu Zhenru, Yuan Jingsheng, Yang Jian
Laboratory of Liquid Biopsy and Single Cell Research, Department of Radiation Oncology and Department of Head and Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Institute of Organ Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
Biochem Pharmacol. 2025 Jun;236:116887. doi: 10.1016/j.bcp.2025.116887. Epub 2025 Mar 19.
Cancer stem cells (CSCs) play an essential role in tumor initiation and therapy resistance. Histone lactylation as a novel epigenetic modification could regulate the gene transcription process during tumor progression. Nevertheless, researches have not well examined its role in maintaining CSC properties. Our study identified Minichromosome maintenance complex component 7 (MCM7) as a candidate gene in Hepatocellular carcinoma (HCC) with diagnostic and prognostic values, and Real-time quantitative PCR (qRT-PCR), Western blot (WB), and Immunohistochemistry (IHC) assays ascertained its obviously higher expressions in HCC cells and tissues. Ectopic of MCM7 could increase the expression of CSC-related genes and enhance spheroid both in size and in number. Suppression of MCM7 could strengthen the efficacy of radiotherapy verified by Cell counting kit-8 (CCK-8) and colony formation assays. The subcutaneous xenograft model indicated that suppression of MCM7 could inhibit CSC properties and the efficacy of radiotherapy in vivo. Mechanistically, histone lactylation could facilitate MCM7 expression, and both messenger RNA (mRNA) and protein level of MCM7 expression presented an obvious decrease due to 2-DG (glycolysis inhibitor) treatment and an obvious increase due to Rotenone (glycolysis activator) treatment. Rescue experiments verified that histone lactylation was necessary for MCM7 to promote CSC properties and radio-resistance in HCC. Arsenic trioxide (ATO) targeting MCM7 could inhibit the CSC phenotypes and enhance the efficacy of radiotherapy in vivo and in vitro. Collectively, histone lactylation could transcriptionally activate MCM7 to accelerate proliferation and radio-resistance through enhancing CSC properties. ATO targeting MCM7 could inhibit CSCs phenotypes and synergistically increase the efficacy of radiation therapy.
癌症干细胞（CSCs）在肿瘤起始和治疗抗性中起着至关重要的作用。组蛋白乳酰化作为一种新的表观遗传修饰，可在肿瘤进展过程中调节基因转录过程。然而，尚未有研究充分探究其在维持CSC特性中的作用。我们的研究确定微小染色体维持复合物组分7（MCM7）为肝细胞癌（HCC）中的一个具有诊断和预后价值的候选基因，实时定量聚合酶链反应（qRT-PCR）、蛋白质免疫印迹（WB）和免疫组织化学（IHC）分析确定其在HCC细胞和组织中的表达明显更高。异位表达MCM7可增加CSC相关基因的表达，并在大小和数量上增强球体形成。抑制MCM7可增强放射治疗的疗效，这通过细胞计数试剂盒-8（CCK-8）和集落形成分析得到验证。皮下异种移植模型表明，抑制MCM7可在体内抑制CSC特性和放射治疗的疗效。机制上，组蛋白乳酰化可促进MCM7表达，MCM7表达的信使核糖核酸（mRNA）和蛋白质水平因2-脱氧葡萄糖（糖酵解抑制剂）处理而明显降低，因鱼藤酮（糖酵解激活剂）处理而明显升高。挽救实验证实，组蛋白乳酰化是MCM7促进HCC中CSC特性和放射抗性所必需的。靶向MCM7的三氧化二砷（ATO）可在体内外抑制CSC表型并增强放射治疗的疗效。总的来说，组蛋白乳酰化可通过增强CSC特性转录激活MCM7以加速增殖和放射抗性。靶向MCM7的ATO可抑制CSC表型并协同提高放射治疗的疗效。
