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CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-beta signaling
Zhiqiang Zhao1; Dapeng Hao1,5; Li Wang1,2; Jingjing Li1; Yuan Meng1; Peipei Li1; Yuan Wang1; Chao Zhang1; Haisheng Zhou3; Kevin Gardner4; Li-jun Di1
2018-11-15
Source PublicationONCOGENE
ISSN0950-9232
Volume38Issue:12Pages:2076-2091
Abstract

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.

DOI10.1038/s41388-018-0570-z
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS SubjectBiochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS IDWOS:000461822600006
PublisherNATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
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Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorLi-jun Di
Affiliation1.Cancer Center, Faculty of Health Sciences, University of Macau, Macau, China
2.Metabolomics Core, Faculty of Health Sciences, University of Macau, Macau, China
3.Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China
4.Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, USA
5.Present address: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Zhiqiang Zhao,Dapeng Hao,Li Wang,et al. CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-beta signaling[J]. ONCOGENE,2018,38(12):2076-2091.
APA Zhiqiang Zhao.,Dapeng Hao.,Li Wang.,Jingjing Li.,Yuan Meng.,...&Li-jun Di.(2018).CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-beta signaling.ONCOGENE,38(12),2076-2091.
MLA Zhiqiang Zhao,et al."CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-beta signaling".ONCOGENE 38.12(2018):2076-2091.
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