肿瘤中HIF1A超级增强子的鉴定及分子机制研究

Cancer seriously threaten the life and health of human，novel therapies are urgently needed. Aerobic glycolysis is one of the main characteristics of cancers. It facilitates the formation of tumor microenvironment in tumors, which accounts for the inefficiency of most current antitumor therapies including immunotherapies. Therefore, revealing the causes of aerobic glycolysis and restraining the tumor microenvironment is of great concern. Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A) is the master regulator of aerobic glycolysis in cancer cells. The over-expression of HIF1A have been found in many types of cancers, however, the underlying mechanism is still unclear. Previously, we have found an abnormal active region at the upstream of HIF1A. According to preliminary experiments, this region could promote the transcription of HIF1A in cancer cells. We inferred that HIF1A has a particular super-enhancer to support aerobic glycolysis in cancer cells. This project will identified the super-enhancer region of HIF1A (HSE) in cancer cells and validated its homology in multiple types of cancers through bioinformation and biological experiment. Furthermore, we will explore the upstream regulators of HSE and their molecular mechanisms of activation. The discovery of the super-enhancer region of HIF1A will contribute to revealing the causes of aerobic glycolysis in cancers. This point can be a new therapeutic target in multiple types of cancers which help to solve the bottleneck of the therapy in solid tumors. The results will provide new ideas and experimental evidences for fundamental research and immunotherapy of cancer.

恶性肿瘤严重威胁人类的生命和健康，加快肿瘤治疗的研究迫在眉睫。有氧糖酵解是恶性肿瘤的主要特征之一，不仅促使形成肿瘤微环境以满足其生长和生存，还能阻碍肿瘤的药物和免疫治疗。揭示肿瘤有氧糖酵解的原因将是实体瘤治疗的关键突破点。HIF1A是有氧糖酵解的核心因子且在多种肿瘤中高表达，但具体的原因和机制仍不明确。本课题组前期发现肿瘤中HIF1A基因上游非编码区存在异常开放的染色体区域，并初步证明此区域促进了HIF1A的表达。据此推断，肿瘤细胞中存在特殊的超级增强子来促进HIF1A的表达。本项目将通过生物信息和生物学实验鉴定HIF1A在肿瘤细胞中的超级增强子区域及其在多种肿瘤中的同源性，并深入研究此超级增强子激活和作用的分子机制。HIF1A超级增强子的发现有助于阐明肿瘤有氧糖酵解的原因，该位点可作为多种类型肿瘤的新治疗靶点从而解决实体瘤治疗的瓶颈问题，为肿瘤的基础研究和免疫治疗提供新的思路和实验依据。

肿瘤细胞不但在缺氧缺血的环境下有较强的适应力，而且在有氧的情况下依然维持高度的糖酵解。作为恶性肿瘤的主要特征之一，有氧糖酵解可促使实体瘤内部形成肿瘤微环境以满足其生长和生存，还能阻碍药物和免疫治疗的进行。肿瘤高度糖酵解的原因和机制尚未完全解析。HIF1A是糖酵解的核心转录因子，在多种肿瘤中高表达，本课题发现了多种肿瘤细胞中HIF1A基因上游非编码区存在一个超级增强子，通过基因编辑技术和三维基因组学证明了此区域可以显著提高HIF1A的转录。体内体外实验表明此超级增强子可以促进肿瘤发生发展。并进一步研究了此超级增强子激活和作用的分子机制，揭示了肿瘤细胞维持高度糖酵解水平的原因，为肿瘤的基础研究和免疫治疗提供新的思路和靶点。