Despite the importance of mitochondrial fatty acid oxidation (FAO) in cancer metabolism, the biological mechanisms responsible for the FAO in cancer and therapeutic intervention based on catabolic metabolism are not well defined. In this study, we observe that Snail (SNAI1), a key transcriptional repressor of epithelial-mesenchymal transition, enhances catabolic FAO, allowing pro-survival of breast cancer cells in a starved environment. Mechanistically, Snail suppresses mitochondrial ACC2 (ACACB) by binding to a series of E-boxes located in its proximal promoter, resulting in decreased malonyl-CoA level. Malonyl-CoA being a well-known endogenous inhibitor of fatty acid transporter carnitine palmitoyltransferase 1 (CPT1), the suppression of ACC2 by Snail activates CPT1-dependent FAO, generating ATP and decreasing NADPH consumption. Importantly, combinatorial pharmacologic inhibition of pentose phosphate pathway and FAO with clinically available drugs efficiently reverts Snail-mediated metabolic reprogramming and suppresses in vivo metastatic progression of breast cancer cells. Our observations provide not only a mechanistic link between epithelial-mesenchymal transition and catabolic rewiring but also a novel catabolism-based therapeutic approach for inhibition of cancer progression.
Bibliographical noteFunding Information:
We thank E Tunkle for preparation of the manuscript and KY Kim for statistical analysis. We also thank HG Kim at Avison Biomedical Research Center for technical assistance with the lung metastasis assay. This work was supported by grants from the National Research Foundation of Korea (NRF-2016R1E1A1A01942724, NRF-2017R1A2B3002241, NRF-2018M3A9E2022820, NRF-2018R1D1A1B07050744, and NRF-2019R1A2C2084535) funded by the Korea government (MSIP), a grant from the Korean Health Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI17C2586), and a grant from the Yonsei University College of Dentistry Fund (6-2018-0006).
© 2020 Yang et al.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Plant Science
- Health, Toxicology and Mutagenesis