Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer.

Ser Yue Loo, Li Ping Toh, William Haowei Xie, Elina Pathak, Wilson Tan, Siming Ma, May Yin Lee, S Shatishwaran, Joanna Zhen Zhen Yeo, Ju Yuan, Yin Ying Ho, Esther Kai Lay Peh, Magendran Muniandy, Federico Torta, Jack Chan, Tira J Tan, Yirong Sim, Veronique Tan, Benita Tan, Preetha Madhukumar, Wei Sean Yong, Kong Wee Ong, Chow Yin Wong, Puay Hoon Tan, Yoon Sim Yap, Lih-Wen Deng, Rebecca Dent, Roger Foo, Markus R Wenk, Soo Chin Lee, Ying Swan Ho, Elaine Hsuen Lim, Wai Leong Tam

Science advances 2021 Oct 08

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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.

Citation

PMID: 34613780

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