Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Pingping Zhang
Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Wei Liu
Department of Breast Surgery, Guangzhou Red Cross Hospital, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
Guorong Liu
Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Juan Zhang
Department of Laboratory Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Min Yan
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic–metabolic feedback loop between the epithelial–mesenchymal transition transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation (FAO) to drive breast cancer metastasis. Functionally, depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LDs) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2-activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and LDs accumulation but also enhances FAO and adenosine triphosphate production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LDs storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2–ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis.
