NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis
NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis
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NSDHL通过TGF β信号通路和胆固醇生物合成促进三阴性乳腺癌转移
DOI：
10.1007/s10549-021-06213-8
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发表时间：
2021-04-16
影响因子：
3.8
通讯作者：
Jin, Wei
中科院分区：
文献类型：
--
作者：
Chen, Mengting;Zhao, Yang;Jin, Wei
目的转移是乳腺癌死亡的主要原因。近年来的研究表明，脂质代谢重编程在乳腺癌的发生和转移中起着至关重要的作用。我们的目标是确定乳腺癌转移的关键脂质代谢基因。方法设计并克隆含脂代谢基因引导rna的CRISPR池文库，并在体内进行遗传筛选。采用Transwell法和动物实验分别评价细胞在体外和体内的转移能力。我们利用乳腺癌组织芯片进行免疫组化研究NSDHL的临床意义。我们发现一种胆固醇代谢酶NSDHL是三阴性乳腺癌的潜在转移驱动因素。NSDHL在乳腺癌组织中高表达，预后较差。敲低NSDHL可显著抑制细胞增殖和迁移。机制上，NSDHL通过抑制TGF β R2的内体降解激活TGF β信号通路。此外，酮康唑阻断NSDHL上游代谢可挽救肿瘤转移和TGF β R2降解。然而，NSDHL （Y151X）的失活并不能挽救其迁移能力和TGF β R2蛋白的表达。综上所述，我们的研究结果表明NSDHL是一种转移驱动因子，其功能取决于其在胆固醇生物合成中的酶活性，并由NSDHL- tgf β R2信号通路介导。我们的研究表明NSDHL和类固醇生物合成可能成为晚期乳腺癌患者新的药物靶点。
Purpose Metastasis is the main cause of breast cancer mortality. Recent studies have proved that lipid metabolic reprogramming plays critical roles in breast cancer carcinogenesis and metastasis. We aim to identify critical lipid metabolism genes in breast cancer metastasis. Methods We designed and cloned a CRISPR pooled library containing lipid metabolic gene guide RNAs and performed a genetic screen in vivo. Transwell assay and animal experiments were used to evaluate cell metastatic ability in vitro or in vivo, respectively. We performed immunohistochemistry with breast cancer tissue microarray to study the clinical significance of NSDHL. Findings We identified a cholesterol metabolic enzyme, NSDHL, as a potential metastatic driver in triple-negative breast cancer. NSDHL was highly expressed in breast cancer tissues and predicted a poor prognosis. NSDHL knockdown significantly suppressed cell proliferation and migration. Mechanistically, NSDHL activated the TGF beta signaling pathway by inhibiting the endosomal degradation of TGF beta R2. In addition, blocking the upstream metabolism of NSDHL with ketoconazole rescued cancer metastasis and TGF beta R2 degradation. However, the inactivation of NSDHL (Y151X) did not rescue the migration ability and the TGF beta R2 protein expression. Conclusion Taken together, our findings established that NSDHL serves as a metastatic driver, and its function depends on its enzyme activity in cholesterol biosynthesis and is mediated by the NSDHL-TGF beta R2 signal pathway. Our study indicated that NSDHL and steroid biosynthesis may serve as new drug targets for patients with advanced breast cancer.