SerRS在三阴性乳腺癌脂代谢失调中的作用机制及靶向干预

脂质物质从头合成及氧化降解的异常激活在三阴性乳腺癌（TNBC）的恶性增殖、转移和耐药中均有重要作用，但其失调的机制还远未明晰。已有研究表明蛋白质合成能通过非折叠蛋白质反应（UPR）协同调控脂肪代谢，其失控与肥胖及肿瘤等密切相关。我们前期研究发现蛋白质合成重要酶SerRS能进细胞核抑制脂肪代谢关键基因的转录而完全抑制TNBC细胞增殖，且其入核受代谢应激和乙酰化调控，提示SerRS在“代谢应激-UPR-脂代谢”的调控轴中发挥重要作用。本项目拟在此基础上，1）利用代谢组学和转录组学等方法进一步在SerRS乙酰化及入核缺陷型小鼠（SerRS-K/R）、移植瘤模型和临床样本上深入研究SerRS在TNBC脂质合成和氧化异常激活中的作用和机制；2）鉴定代谢应激调控SerRS乙酰化和入核的重要乙酰化酶和去乙酰化酶；3）靶向SerRS表达及乙酰化修饰，开发重塑TNBC脂代谢平衡的小分子药物。

Abnormally elevated de novo lipid synthesis and oxidative degradation play essential roles in the malignant transformation, growth, metastasis and drug resistance of the triple-negative breast cancer (TNBC). However, the mechanisms underlying the dysregulated lipid metabolism in TNBC remain largely unknown. ER stress and unfolded protein response (UPR) caused by dysregulated protein homeostasis have been well established to be a key pathway regulating the lipid metabolism to maintain the ER homeostasis and are linked to many metabolic disorders including obesity and cancers. We previously discovered a novel function of a key enzyme in protein biosynthesis, i.e., seryl tRNA synthetase (SerRS), which can translocate to the nucleus to suppress the transcription of many genes encoding key enzymes involved in lipid metabolism and consequently strongly inhibit the proliferation of TNBC cells. And the nuclear translocation of SerRS is affected by metabolic stresses, such as the deficiency in nutrients like glucose, and subsequent acetylation modification on SerRS, suggesting SerRS is a key mediator in ‘metabolic stress-UPR-lipid metabolism’ axis. Based on these findings, we proposed in this project to: 1) further study the regulatory roles of SerRS in the activation of lipid de novo synthesis and oxidative degradation in TNBC in vivo by lipidomics, transcriptome analysis on acetylation-defective SerRS knock-in mice (SerRS-K/R), TNBC xenograft models and human TNBC specimen; 2) identify key deacetylase and acetyl-transferase involved in metabolic stress-induce acetylation of SerRS in TNBC; 3) develop new small molecule drugs targeting SerRS expression and acetylation to restore the lipid homeostasis in TNBC for its therapy.