Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress

Nam Hee Kim; Yong Hoon Cha; Jueun Lee; Seon Hyeong Lee; Ji Hye Yang; Jun Seop Yun; Eunae Sandra Cho; Xianglan Zhang; Miso Nam; Nami Kim; Young Su Yuk; So Young Cha; Yoonmi Lee; Joo Kyung Ryu; Sunghyouk Park; Jae Ho Cheong; Sang Won Kang; Soo Youl Kim; Geum Sook Hwang; Jong In Yook; Hyun Sil Kim

doi:10.1038/ncomms14374

Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress

Nam Hee Kim, Yong Hoon Cha, Jueun Lee, Seon Hyeong Lee, Ji Hye Yang, Jun Seop Yun, Eunae Sandra Cho, Xianglan Zhang, Miso Nam, Nami Kim, Young Su Yuk, So Young Cha, Yoonmi Lee, Joo Kyung Ryu, Sunghyouk Park, Jae Ho Cheong, Sang Won Kang, Soo Youl Kim, Geum Sook Hwang, Jong In YookHyun Sil Kim

Life Sciences

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

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.

Original language	English
Article number	14374
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14374
State	Published - 8 Feb 2017

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF-2012M3A9B2052523, NRF-2014R1A2A1A05004670, NRF-2016R1E1A1A01942724) funded by the Korea government (MSIP), a grant from the National Research Foundation of Korea (NRF-2014R1A6A3A04055110) funded by the Korea government (MOE), and a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1420310). This work was also supported by the by the National Research Council of Science & Technology (CAP-2012-2-KBSI), and the Korea Basic Science Institute (C36705). S.Y. Kim was supported by a grant from the National Cancer Center of Korea (NCC1410670).

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© The Author(s) 2017.

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Kim, N. H., Cha, Y. H., Lee, J., Lee, S. H., Yang, J. H., Yun, J. S., Cho, E. S., Zhang, X., Nam, M., Kim, N., Yuk, Y. S., Cha, S. Y., Lee, Y., Ryu, J. K., Park, S., Cheong, J. H., Kang, S. W., Kim, S. Y., Hwang, G. S., ... Kim, H. S. (2017). Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress. Nature Communications, 8, Article 14374. https://doi.org/10.1038/ncomms14374

@article{d40babf084a04c3fa5bbe24bb4955e31,

title = "Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress",

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.",

author = "Kim, {Nam Hee} and Cha, {Yong Hoon} and Jueun Lee and Lee, {Seon Hyeong} and Yang, {Ji Hye} and Yun, {Jun Seop} and Cho, {Eunae Sandra} and Xianglan Zhang and Miso Nam and Nami Kim and Yuk, {Young Su} and Cha, {So Young} and Yoonmi Lee and Ryu, {Joo Kyung} and Sunghyouk Park and Cheong, {Jae Ho} and Kang, {Sang Won} and Kim, {Soo Youl} and Hwang, {Geum Sook} and Yook, {Jong In} and Kim, {Hyun Sil}",

note = "Funding Information: This work was supported by grants from the National Research Foundation of Korea (NRF-2012M3A9B2052523, NRF-2014R1A2A1A05004670, NRF-2016R1E1A1A01942724) funded by the Korea government (MSIP), a grant from the National Research Foundation of Korea (NRF-2014R1A6A3A04055110) funded by the Korea government (MOE), and a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1420310). This work was also supported by the by the National Research Council of Science & Technology (CAP-2012-2-KBSI), and the Korea Basic Science Institute (C36705). S.Y. Kim was supported by a grant from the National Cancer Center of Korea (NCC1410670). Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

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day = "8",

doi = "10.1038/ncomms14374",

language = "English",

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journal = "Nature Communications",

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Kim, NH, Cha, YH, Lee, J, Lee, SH, Yang, JH, Yun, JS, Cho, ES, Zhang, X, Nam, M, Kim, N, Yuk, YS, Cha, SY, Lee, Y, Ryu, JK, Park, S, Cheong, JH, Kang, SW, Kim, SY, Hwang, GS, Yook, JI & Kim, HS 2017, 'Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress', Nature Communications, vol. 8, 14374. https://doi.org/10.1038/ncomms14374

TY - JOUR

T1 - Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress

AU - Kim, Nam Hee

AU - Cha, Yong Hoon

AU - Lee, Jueun

AU - Lee, Seon Hyeong

AU - Yang, Ji Hye

AU - Yun, Jun Seop

AU - Cho, Eunae Sandra

AU - Zhang, Xianglan

AU - Nam, Miso

AU - Kim, Nami

AU - Yuk, Young Su

AU - Cha, So Young

AU - Lee, Yoonmi

AU - Ryu, Joo Kyung

AU - Park, Sunghyouk

AU - Cheong, Jae Ho

AU - Kang, Sang Won

AU - Kim, Soo Youl

AU - Hwang, Geum Sook

AU - Yook, Jong In

AU - Kim, Hyun Sil

N1 - Funding Information: This work was supported by grants from the National Research Foundation of Korea (NRF-2012M3A9B2052523, NRF-2014R1A2A1A05004670, NRF-2016R1E1A1A01942724) funded by the Korea government (MSIP), a grant from the National Research Foundation of Korea (NRF-2014R1A6A3A04055110) funded by the Korea government (MOE), and a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1420310). This work was also supported by the by the National Research Council of Science & Technology (CAP-2012-2-KBSI), and the Korea Basic Science Institute (C36705). S.Y. Kim was supported by a grant from the National Cancer Center of Korea (NCC1410670). Publisher Copyright: © The Author(s) 2017.

PY - 2017/2/8

Y1 - 2017/2/8

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms14374

DO - 10.1038/ncomms14374

M3 - Article

C2 - 28176759

AN - SCOPUS:85012004868

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14374

ER -

Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress

Abstract

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