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Snail augments fatty acid oxidation by suppression of mitochondrial ACC2 during cancer progression

 Ji Hye Yang  ;  Nam Hee Kim  ;  Jun Seop Yun  ;  Eunae Sandra Cho  ;  Yong Hoon Cha  ;  Sue Bean Cho  ;  Seon-Hyeong Lee  ;  So Young Cha  ;  Soo-Youl Kim  ;  Jiwon Choi  ;  Tin-Tin Manh Nguyen  ;  Sunghyouk Park  ;  Hyun Sil Kim  ;  Jong In Yook 
 LIFE SCIENCE ALLIANCE, Vol.3(7) : e202000683, 2020-07 
Journal Title
Issue Date
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.
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2. College of Dentistry (치과대학) > Dept. of Oral and Maxillofacial Surgery (구강악안면외과학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Research Institute (부설연구소) > 1. Journal Papers
Yonsei Authors
Kim, Nam Hee(김남희) ORCID logo https://orcid.org/0000-0002-3087-5276
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Cho, Eunae(조은애산드라) ORCID logo https://orcid.org/0000-0002-0820-3019
Cha, So Young(차소영) ORCID logo https://orcid.org/0000-0002-2810-3883
Cha, Yong Hoon(차용훈) ORCID logo https://orcid.org/0000-0003-1761-3260
Choi, Jiwon(최지원)
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