Histone lactylation facilitates hepatocellular carcinoma progression by upregulating endothelial cell-specific molecule 1 expression.

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-11-01 Epub Date: 2024-07-17 DOI:10.1002/mc.23794
Peng Zhao, Chunzhong Qiao, Jiawei Wang, Ye Zhou, Changhe Zhang
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Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor. Histone lactylation, a novel epigenetic modification, plays a crucial role in various cancers. However, the functional role and underlying mechanism of histone lactylation in HCC progression have not yet been investigated. Histone lactylation levels in HCC tissues and cells were assessed using a densitometric kit and western blot analysis. The role of histone lactylation in cell malignant phenotypes was determined through functional assays in vitro, and a xenograft tumor model was established to verify the function of histone lactylation in vivo. ChIP assay was performed to explore the interaction between histone lactylation and endothelial cell-specific molecule 1 (ESM1). Additionally, gain-and-loss-of-function assays were conducted to investigate the regulatory role of ESM1 in HCC pathogenesis. Histone lactylation levels were increased in HCC tissues and cells, and H3K9 lactylation (H3K9la) and H3K56 lactylation (H3K56la) were identified as the histone modification sites. We observed that H3K9la and H3K56la caused abnormal histone lactylation and were associated with poor prognosis. Functionally, histone lactylation was found to promote HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro. However, histone lactylation inhibition with 2-deoxy-d-glucose (2-DG) reduced the malignant phenotypes of HCC cells. In vivo, 2-DG treatment reduced tumor growth and metastasis in the HCC mouse model. Mechanistically, it was revealed that histone lactylation activated ESM1 transcription in HCC cells. ESM1 was expressed at a high level in HCC and exerted a carcinogenic role. Histone lactylation facilitates cell malignant phenotypes, tumor growth, and metastasis by upregulating ESM1 expression in HCC, which reveals the downstream molecular mechanism of histone lactylation and might provide a novel therapeutic target for HCC therapy.

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组蛋白乳酰化通过上调内皮细胞特异性分子 1 的表达促进肝细胞癌的进展。
肝细胞癌(HCC)是一种常见的恶性肿瘤。组蛋白乳化是一种新型的表观遗传修饰,在各种癌症中发挥着至关重要的作用。然而,组蛋白乳化在 HCC 进展中的功能作用和内在机制尚未得到研究。我们使用密度测定试剂盒和 Western 印迹分析法评估了 HCC 组织和细胞中组蛋白乳化水平。通过体外功能测试确定了组蛋白乳化在细胞恶性表型中的作用,并建立了异种移植肿瘤模型来验证组蛋白乳化在体内的功能。组蛋白乳化与内皮细胞特异性分子 1(ESM1)之间的相互作用是通过 ChIP 法检测的。此外,还进行了功能增益和功能缺失试验,以研究ESM1在HCC发病机制中的调控作用。HCC组织和细胞中组蛋白乳化水平升高,H3K9乳化(H3K9la)和H3K56乳化(H3K56la)被确定为组蛋白修饰位点。我们观察到,H3K9la 和 H3K56la 导致组蛋白乳化异常,并与不良预后相关。从功能上看,组蛋白乳化在体外促进了 HCC 细胞的增殖、迁移、侵袭和上皮-间质转化(EMT)过程。然而,用2-脱氧葡萄糖(2-DG)抑制组蛋白乳化可减少HCC细胞的恶性表型。在体内,2-DG 可减少 HCC 小鼠模型的肿瘤生长和转移。研究发现,组蛋白乳化激活了 HCC 细胞中 ESM1 的转录。ESM1在HCC中高水平表达并发挥致癌作用。组蛋白乳化通过上调ESM1在HCC中的表达,促进细胞恶性表型、肿瘤生长和转移,这揭示了组蛋白乳化的下游分子机制,并可能为HCC治疗提供一个新的治疗靶点。
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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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