组蛋白伴侣FACT通过SAT1调控多胺代谢抑制胆管癌细胞铁死亡的机制探究

胆管癌是一种恶性程度很高的肿瘤，目前药物治疗效果有限，晚期患者生存率仅10%左右，因此寻找新的治疗靶点是亟需解决的问题。我们前期通过大数据分析发现，组蛋白伴侣FACT在胆管癌组织中高表达，抑制FACT可以抑制胆管癌细胞的增殖，RNA测序显示这种作用与谷胱甘肽代谢、脂质代谢的改变有关，提示抑制FACT可以通过诱导脂质过氧化促进铁死亡。同时抑制FACT可增加亚精胺/精胺乙酰转移酶SAT1的表达，有研究表明SAT1参与调控细胞铁死亡，但目前FACT对SAT1的调控及其在胆管癌中的作用机制尚不明确。本研究拟基于以患者来源的裸鼠移植瘤模型，评估FACT的小分子抑制剂CBL0137的体内抗胆管癌作用，并通过CRISPR/Cas9技术构建稳定沉默及过表达FACT的胆管癌细胞，探讨抑制FACT通过激活SAT1、调节多胺代谢、诱导铁死亡的机制，为靶向抑制FACT的抗胆管癌策略提供科学依据。

Cholangiocarcinoma (CCA) is a fatal disease and still lack of effective therapeutics. Our previous work has shown that FACT, a member of histone chaperone, was overexpressed in CCA. Inhibition of FACT inhibited cell proliferation, which may caused by glutathione metabolism and the lipid metabolism. It could induce lipid peroxidation, indicating the antitumor effect through ferroptosis. RNA sequencing demonstrated that Spermidine/spermine acetyltransferase(SAT1) was enhanced by FACT inhibitor, CBL0137. Currently, the biologic role of FACT and its regulation of SAT1 in CCA is still unknown. This project is going to evaluate the effect of CBL0137 in patient-derived xenograft (PDX) model. Meanwhile, we will investigate the mechanism of FACT in regulating polyamine metabolism via SAT1 and inducing ferroptosis, based on CRISPR/Cas9 technology. Our goal is to reveal the antitumor efficacy of FACT inhibition in CCA and provide scientific evidence of targeting FACT for CCA treatment.