Cancer Center, Faculty of Health Sciences, University of Macau, Macau, China.
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Oncogene. 2019 Mar;38(12):2076-2091. doi: 10.1038/s41388-018-0570-z. Epub 2018 Nov 15.
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.
转移是原发性癌细胞扩散到原发性肿瘤以外并传播到其他器官的过程。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初始事件，而它是如何发生的仍然是一个谜。CtBP 是一种在许多类型的癌症中大量表达的共抑制因子，它调节与癌症起始、进展和转移相关的基因。我们发现 CtBP 通过与 ZEB1 形成复合物并转录抑制 SREBF2 的表达来调节乳腺癌细胞内的胆固醇稳态。重要的是，CtBP 对细胞内胆固醇丰度的抑制导致 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 也能够通过增加 ZEB1 和 CtBP 复合物向 SREBF2 启动子的募集来减少细胞内胆固醇。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回路，通过这个回路，TGF-β 触发了动员癌细胞转移的级联反应。一致地，过表达 CtBP 的乳腺癌细胞静脉注射后，由于细胞内胆固醇的减少，肺转移增加。最后，我们分析了公共乳腺癌数据集，发现 CtBP 表达与 SREBF2 和 HMGCR 的表达呈负相关。CtBP 高表达和 SREBF2 和 HMGCR 低表达与原发性肿瘤的高 EMT 显著相关。
