Nam Hee Kim1,*, Yong Hoon Cha1,*,†, Jueun Lee2,3, Seon-Hyeong Lee4, Ji Hye Yang1, Jun Seop Yun1, Eunae Sandra Cho1, Xianglan Zhang1,5, Miso Nam2,3, Nami Kim2, Young-Su Yuk1, So Young Cha1, Yoonmi Lee1, Joo Kyung Ryu1, Sunghyouk Park6, Jae-Ho Cheong7, Sang Won Kang8, Soo-Youl Kim4, Geum-Sook Hwang2, Jong In Yook1 & Hyun Sil Kim1
1Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea. 2Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Korea. 3Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea. 4Cancer Cell and Molecular Biology Branch, National Cancer Center, Ilsan 10408, Korea. 5Department of Pathology, Yanbian University Medical College, Yanji City, Jilin Province 133000, China. 6College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea. 7Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea. 8Department of Life Sciences, Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea.
* These authors contributed equally to this work.
† Present address: Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 120-752, Korea.
Correspondence and requests for materials should be addressed to G-S.H. or to J.I.Y. or to H.S.K..
Abstract
Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial–mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of phosphofructokinase, platelet (PFKP), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.