前期大量研究(包括我们发表的文章)已证明，癌蛋白Bmi-1可通过多种分子机制促进肿瘤的发生发展，如诱导永生化，促使恶性转化，诱发上皮细胞间质化，维持肿瘤干细胞自我更新能力等。并且多个转录上调Bmi-1的转录因子及多个抑制Bmi-1蛋白翻译的miRNAs都已被证明与肿瘤的发生发展密切相关。然而Bmi-1蛋白的翻译后修饰方式及不同修饰方式产生的生物学效应，目前仍为空白。近期结合免疫共沉淀耦联质谱等多种方法，我们发现：经①乙酰化酶CBP乙酰化修饰或②泛素化连接酶MDM2单泛素化修饰后，Bmi-1蛋白癌功能显著增强；③GSK-3β激酶可磷酸化并促进Bmi-1蛋白降解，而SPHK1激酶磷酸化Bmi-1蛋白却可抑制其降解。同时④Bmi-1可多泛素化降解USP16蛋白而维持组蛋白2A的单泛素化。本研究将承前启后，深层次解析Bmi-1蛋白翻译后的修饰方式及其生物学效应，为肿瘤治疗提供科学依据及新的靶位点。

Mounting evidence, including our published results, have shown that the onco-protein Bmi-1 promotes the development and progression of cancer through multiple molecular mechanisms, such as promotion of cell immortalization and malignant transformation, induction of epithelial-mesenchymal transition (EMT), and maintenance of the capacity for cancer stem cell self-renewal. It has also been reported that numbers of transcription transcription factors and miRNAs play roles in tumor progression through the regulation of Bmi-1. However, the biological effects of different post-translational modifications of Bmi-1 are still largely unknown. Preliminary data obtained from co-immunoprecipitation experiments with coupled mass spectrometry (Co-IP/MS) showed that acetylation by the acetylase CBP, or ubiquitination by the ubiquitin ligase MDM2, could enhance the oncogenic properties of Bmi-1; GSK-3β kinase phosphorylates and promotes Bmi-1 protein degradation, whereas phosphorylation of Bmi-1 by SPHK1 kinase stabilizes Bmi-1 protein. Moreover, we found that Bmi-1 could also induce USP16 degradation through polyubiqutination and maintain the mono-ubiqutination of histone 2A. In the current project, we aim to investigate the mechanisms and biological effects of post-modifications of Bmi-1 on cancer progression, which would to provide novel targets in cancer therapy.