醛缩酶B调控CtBP2二聚化抑制肾透明细胞癌增殖的机制研究

代谢重编程是肾透明细胞癌的重要特征。而差异表达的代谢酶是否通过其兼职（非代谢）功能影响肿瘤进展尚不明确。我们前期发现醛缩酶B在肾透明细胞癌中具有不依赖其代谢酶活性的肿瘤增殖抑制功能，并且醛缩酶B在肾透明细胞癌组织中表达显著下调。我们通过串联亲和纯化-质谱在肾透明细胞癌细胞中鉴定发现辅抑制因子CtBP2是一种醛缩酶B互作蛋白，而活化的CtBP2可抑制下游多个细胞周期、促凋亡基因的转录，促进肿瘤发展。初步实验证实，醛缩酶B与CtBP2的羟酸脱氢酶同源结构域（负责二聚化）结合；醛缩酶B能够抑制CtBP2的二聚化。而二聚化是CtBP2活化的关键因素之一。由此我们提出假说：醛缩酶B通过调控CtBP2二聚化从而抑制肾透明细胞癌增殖。本项目拟在细胞和动物模型中进一步深入解析醛缩酶B与CtBP2的互作模式，揭示醛缩酶B的非代谢功能与详细机制，为开发肾透明细胞癌治疗的新靶点提供科学依据。

Metabolic reprogramming is an important feature of clear cell renal cell carcinoma. It is unclear whether differentially expressed metabolic enzymes affect tumor progression through their moonlighting (non-metabolic) functions. We have previously found that aldolase B inhibited proliferation independent of enzyme activity in clear cell renal cell carcinoma, and aldolase B was significantly down-regulated in clear cell renal cell carcinoma tissues; we identified the corepressor CtBP2 as a novel aldolase B interacting protein in clear cell renal cell carcinoma through tandem affinity purification-mass spectrometry, and it is known that activated CtBP2 can inhibit the transcription of multiple cell-cycle inhibitors and pro-apoptotic genes, and promote tumor development. Preliminary experiments confirmed that aldolase B bound to the hydroxyacid dehydrogenase homology domain (responsible for dimerization) of CtBP2; aldolase B could inhibit the dimerization of CtBP2, which is a key factor in the activation of CtBP2. Therefore, we propose a hypothesis that aldolase B inhibits the proliferation of clear cell renal cell carcinoma by regulating CtBP2’s dimerization. This project aims to gain more insight into the aldolase B / CtBP2 interactions in cell and animal models, reveal the non-metabolic function of aldolase B, explore detailed mechanisms, and provide scientific evidence for developing new targets of cancer treatment.