Metastasis is the process through which the primary cancer cells spread beyond the primary tumor and disseminate to other organs. Most cancer patients die of metastatic disease. EMT is proposed to be the initial event associated with cancer metastasis and how it occurred is still a mystery. CtBP is known as a co-repressor abundantly expressed in many types of cancer and regulates genes involved in cancer initiation, progression, and metastasis. We found that CtBP regulates intracellular cholesterol homeostasis in breast cancer cells by forming a complex with ZEB1 and transcriptionally repressing SREBF2 expression. Importantly, CtBP repression of intracellular cholesterol abundance leads to increased EMT and cell migration. The reason is that cholesterol negatively regulates the stability of TGF-β receptors on the cell membrane. Interestingly, TGF-β is also capable of reducing intracellular cholesterol relying on the increased recruitment of ZEB1 and CtBP complex to SREBF2 promoter. Thus, we propose a feedback loop formed by CtBP, cholesterol, and TGF-β signaling pathway, through which TGF-β triggers the cascade that mobilizes the cancer cells for metastasis. Consistently, the intravenous injection of breast cancer cells with ectopically CtBP expression show increased lung metastasis depending on the reduction of intracellular cholesterol. Finally, we analyzed the public breast cancer datasets and found that CtBP expression negatively correlates with SREBF2 and HMGCR expressions. High expression of CtBP and low expression of SREBF2 and HMGCR significantly correlates with high EMT of the primary tumors.

中文翻译：

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CtBP通过抑制胆固醇和激活TGF-β信号传导来促进乳腺癌的转移。

转移是原发癌细胞扩散到原发肿瘤之外并扩散到其他器官的过程。大多数癌症患者死于转移性疾病。EMT被认为是与癌症转移相关的最初事件，如何发生仍然是一个谜。CtBP被称为在多种类型的癌症中大量表达的协同阻遏物，并调节与癌症发生，发展和转移有关的基因。我们发现CtBP通过与ZEB1形成复合物并转录抑制SREBF2表达来调节乳腺癌细胞中的细胞内胆固醇稳态。重要的是，细胞内胆固醇丰度的CtBP抑制导致EMT和细胞迁移增加。原因是胆固醇负调节细胞膜上TGF-β受体的稳定性。有趣的是，TGF-β还能够依靠增加ZEB1和CtBP复合物募集到SREBF2启动子来降低细胞内胆固醇。因此，我们提出了一个由CtBP，胆固醇和TGF-β信号通路形成的反馈环，TGF-β通过该反馈环触发了动员癌细胞转移的级联反应。一致地，静脉注射具有异位CtBP表达的乳腺癌细胞显示出增加的肺转移，这取决于细胞内胆固醇的降低。最后，我们分析了公共乳腺癌数据集，发现CtBP表达与SREBF2和HMGCR表达负相关。CtBP的高表达和SREBF2和HMGCR的低表达与原发性肿瘤的高EMT显着相关。