PT  - JOURNAL ARTICLE
AU  - Ji Hye Yang
AU  - Nam Hee Kim
AU  - Jun Seop Yun
AU  - Eunae Sandra Cho
AU  - Yong Hoon Cha
AU  - Sue Bean Cho
AU  - Seon-Hyeong Lee
AU  - So Young Cha
AU  - Soo-Youl Kim
AU  - Jiwon Choi
AU  - Tin-Tin Manh Nguyen
AU  - Sunghyouk Park
AU  - Hyun Sil Kim
AU  - Jong In Yook
TI  - Snail augments fatty acid oxidation by suppression of mitochondrial ACC2 during cancer progression
AID  - 10.26508/lsa.202000683
DP  - 2020 Jul 01
TA  - Life Science Alliance
PG  - e202000683
VI  - 3
IP  - 7
4099  - https://www.life-science-alliance.org/content/3/7/e202000683.short
4100  - https://www.life-science-alliance.org/content/3/7/e202000683.full
SO  - Life Sci. Alliance2020 Jul 01; 3
AB  - 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.