肿瘤低氧环境、糖酵解关键酶活性改变及相关信号通路异常与肿瘤发生发展密切相关。丙酮酸激酶2（PKM2）为糖酵解关键限速酶。申请者与合作者前期研究发现乳腺癌中糖酵解增强，PKM2和组蛋白H3磷酸化均显著升高。预试验显示：泛素E3链接酶RNF8通过FHA结构域催化组蛋白H3多聚泛素化，该过程依赖于PKM2；EGF可诱导组蛋白H3泛素化降解。结合申请者前期报道细胞核内PKM2直接催化组蛋白H3磷酸化调控基因转录的发现，我们提出该项课题假设：乳腺癌中高表达的PKM2催化组蛋白H3磷酸化，招募RNF8催化转录激活区组蛋白H3多聚泛素化并使之降解、核小体解聚，进而调控下游基因表达，影响乳腺癌发生发展。本课题将围绕“PKM2-RNF8-组蛋白H3多聚泛素化修饰”这一主线开展深入合作研究。采用分子生物学手段揭示其精细分子机制和对乳腺癌细胞的影响，结合临床数据探讨在乳腺癌诊断和治疗中的应用。

Cancer cells have increased glucose uptake and elevated lactic acid production under aerobic conditions, our research has revealed that pyruvate kinase M2 (PKM2), a glycolytic enzyme has an essential nuclear function in directly regulating tumorigenesis. Our preliminary data show that the binding of the RNF8 forkhead-associated domain to pyruvate kinase M2-phosphorylated histone H3, leading to polyubiquitylation of histone H3 and subsequent proteasome-dependent protein degradation. RNF8-mediated histone H3 polyubiquitylation may play a role in promoting the Warburg effect, cell proliferation, and breast cancer tumorigenesis. Furthermore, clinical correlation between levels of histone H3 expression and post-translational modification with levels of PKM2 and RNF8 are to be examined. This project will highlight the role of PKM2-dependent and RNF8-mediated histone H3 polyubiquitylation in regulation of histone H3 stability and chromatin modification, which is instrumental for epigenetic regulation of gene expression, and thereby systematically elucidate the mechanisms underlying a metabolic enzymes process critical non-metabolic functions in breast cancer tumorigenesis.