Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer
Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high...
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| Veröffentlicht in: | Science advances 2021-10, Vol.7 (41), p.eabh2443-eabh2443 |
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| creator | Loo, Ser Yue Toh, Li Ping Xie, William Haowei Pathak, Elina Tan, Wilson Ma, Siming Lee, May Yin Shatishwaran, S Yeo, Joanna Zhen Zhen Yuan, Ju Ho, Yin Ying Peh, Esther Kai Lay Muniandy, Magendran Torta, Federico Chan, Jack Tan, Tira J Sim, Yirong Tan, Veronique Tan, Benita Madhukumar, Preetha Yong, Wei Sean Ong, Kong Wee Wong, Chow Yin Tan, Puay Hoon Yap, Yoon Sim Deng, Lih-Wen Dent, Rebecca Foo, Roger Wenk, Markus R Lee, Soo Chin Ho, Ying Swan Lim, Elaine Hsuen Tam, Wai Leong |
| description | Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states. |
| doi_str_mv | 10.1126/sciadv.abh2443 |
| format | Article |
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| source | DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Biomedicine and Life Sciences Cancer SciAdv r-articles |
| title | Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer |
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