Although it is becoming increasingly apparent that histone methyltransferases and histone demethylases play crucial roles in the cellular response to hypoxia, the impact of hypoxic environments on global patterns of histone methylation is not well demonstrated. In this study, we try to detect the global levels of histone lysine methylation in HCC cases and analyze the correlation between these modifications and the activation of hypoxia-inducible factor 1α (HIF-1α). Immunohistochemistry was used to detect the global levels of histone H3 lysine 9 dimethylation (H3K9me2), histone H3 lysine 9 trimethylation (H3K9me3), histone H3 lysine 27 trimethylation (H3K27me3) and the nuclear expression of HIF-1α in tissue arrays from 111 paraffin-embedded HCC samples. Our analyses revealed that the global levels of H3K9me2, H3K9me3 and the nuclear expression of HIF-1α were distinctly higher in HCC tissues than in peritumoral tissues. Both H3K9me2 and H3K9me3 were positively correlated with the degree of tumor differentiation and the patients’ prognosis. Analysis based on the Pearson's correlation coefficient indicated a positive correlation between H3K9me2 and the nuclear expression of HIF-1α, and meanwhile, a significant correlation between the expression of H3K9me2 and H3K9me3 was also found. In addition, the combination of H3K9me2, H3K9me3 and HIF-1α, rather than one single histone modification or molecular maker, is a better prognostic maker for HCC patients. These findings provide new insights on the complex networks underlying cellular and genomic regulation in response to hypoxia and may provide novel targets for future therapies.

尽管越来越明显的是，组蛋白甲基转移酶和组蛋白脱甲基酶在细胞对缺氧的反应中起着至关重要的作用，但是低氧环境对组蛋白甲基化的整体模式的影响尚未得到充分证明。在这项研究中，我们试图检测HCC病例中组蛋白赖氨酸甲基化的整体水平，并分析这些修饰与缺氧诱导因子1α（HIF-1α）激活之间的相关性。免疫组化方法检测了111个石蜡组织中H3赖氨酸9的二甲基化（H3K9me2），H3赖氨酸9的三甲基化（H3K9me3），H3赖氨酸27的三甲基化（H3K27me3）的整体水平以及HIF-1α的核表达。嵌入式HCC样本。我们的分析表明，H3K9me2的全球水平 H3K9me3和HIF-1α的核表达在肝癌组织中明显高于肿瘤周围组织。H3K9me2和H3K9me3均与肿瘤的分化程度和患者的预后呈正相关。基于Pearson相关系数的分析表明H3K9me2与HIF-1α的核表达呈正相关，与此同时，H3K9me2与H3K9me3的表达也呈显着相关。此外，H3K9me2，H3K9me3和HIF-1α的组合，而不是单一的组蛋白修饰或分子标记物，是对HCC患者更好的预后标记物。这些发现为应对缺氧的细胞和基因组调控的复杂网络提供了新的见识，并可能为未来的治疗提供新的靶点。