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
Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
Sci Adv. 2021 Oct 8;7(41):eabh2443. doi: 10.1126/sciadv.abh2443. Epub 2021 Oct 6.
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.
细胞状态转变控制着癌细胞的功能行为。上皮-间质转化（EMT）赋予肿瘤细胞癌症干细胞样特性、增强的致瘤性和耐药性，而间质-上皮转化（MET）则逆转这些表型。通过高通量化学文库筛选发现，维甲酸是MET的有效促进剂，可抑制基底样乳腺癌的致瘤性。细胞状态转变由脂质代谢重编程定义。维甲酸与同源核受体结合，这些受体靶向脂质代谢基因，从而将间充质细胞状态下用于β-氧化的脂肪酸重新导向上皮细胞状态下的脂质储存。介导这种通量的关键代谢酶的破坏会抑制MET。相反，对脂肪酸氧化（FAO）的干扰会重新引导脂肪酸通量，并促进更上皮细胞的表型，在动物模型中阻断EMT驱动的乳腺癌转移。FAO通过对EMT基因上组蛋白乙酰化的乙酰辅酶A依赖性调节影响EMT的表观遗传控制，从而决定细胞状态。
