Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress.
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.
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Nam Hee
NH
Kim
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Yong Hoon
YH
Cha
Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Korea.|Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea.
Jueun
J
Lee
Cancer Cell and Molecular Biology Branch, National Cancer Center, Ilsan 10408, Korea.
Seon-Hyeong
SH
Lee
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Ji Hye
JH
Yang
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Jun Seop
JS
Yun
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Eunae Sandra
ES
Cho
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.|Department of Pathology, Yanbian University Medical College, Yanji City, Jilin Province 133000, China.
Xianglan
X
Zhang
Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Korea.|Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea.
Miso
M
Nam
Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Korea.
Nami
N
Kim
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Young-Su
YS
Yuk
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
So Young
SY
Cha
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Yoonmi
Y
Lee
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Joo Kyung
JK
Ryu
College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea.
Sunghyouk
S
Park
Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea.
Jae-Ho
JH
Cheong
Department of Life Sciences, Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea.
Sang Won
SW
Kang
Cancer Cell and Molecular Biology Branch, National Cancer Center, Ilsan 10408, Korea.
Soo-Youl
SY
Kim
Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03760, Korea.
Geum-Sook
GS
Hwang
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Jong In
JI
Yook
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
Hyun Sil
HS
Kim
D002470:Cell Survival / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D009249:NADP / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics*; D010427:Pentose Phosphate Pathway / Q000235:genetics; D010732:Phosphofructokinase-1 / Q000235:genetics* / Q000378:metabolism; D025502:Phosphofructokinase-1, Type C / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D009249:NADP; D025502:Phosphofructokinase-1, Type C; C000628987:PFKP protein, human; D010732:Phosphofructokinase-1; D005947:Glucose