ISG化修饰是一种重要类泛素化修饰，相对其他翻译后修饰，其研究较少。已有部分研究报道了ISG化修饰可影响肿瘤发生发展，但其具体分子机制及关键靶蛋白尚不明确。申请人在前期研究中发现ISG化修饰可抑制部分肿瘤细胞恶性表型，并经蛋白组学分析发现多个蛋白受控于ISG化修饰关键蛋白ISG15。其中EMD蛋白在ISG15过表达及敲减后表达改变明显。代谢组学分析发现ISG15可正调控多个糖代谢途径相关代谢物，并可通过抑制EMD影响肿瘤细胞氧代谢。故猜测：ISG化修饰可通过靶蛋白EMD影响氧代谢，从而改变肿瘤细胞糖代谢，最终起抑癌作用。本项目将明确ISG化修饰通过EMD抑癌，并阐明EMD的ISG化修饰位点及对糖代谢的调控作用，通过临床标本检测明确ISG化修饰及EMD临床意义。本研究将明确ISG化修饰抑癌机制，并为ISG化修饰及靶蛋白EMD作为潜在肿瘤治疗靶点提供依据。

ISGylation is an important ubiquitination-like modification, and it is less studied than other post-translational modifications. Some studies have reported that ISGylation can affect tumor formation and progression, however, its molecular mechanism and key target proteins are still unclear. In previous experiments, the applicant has found that ISGylation inhibits malignant phenotypes of tumor cells, and the proteomics analysis has also revealed some proteins are controlled by ISG15, the key protein of ISGylation. The expression of EMD protein is significantly changed after ISG15 overexpression or knockdown. Metabolomics analysis has showed that ISG15 positively regulates some carbohydrate metabolism pathway-related metabolites and affects tumor cell oxygen metabolism by inhibiting EMD. Therefore, it is hypothesized that ISGylation affects the oxygen metabolism possibly through the target protein EMD, thereby changes the glucose metabolism of tumor cells, and finally inhibits cancer. This project will clarify the mechanism how ISGylation inhibits cancer through EMD, and elucidate the ISGylation site and the regulatory role for glucose metabolism of EMD. The clinical significance of ISGylation and EMD will be revealed through testing of clinical specimen. This study will uncover the anti-cancer mechanism of ISGylation and provide evidence for ISGylation and the target protein EMD as potential targets for cancer treatment.