Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription

Tae Kyu Ha, Nam Gu Her, Min Goo Lee, Byung Kyu Ryu, Jin Hee Lee, Jikhyon Han, Seong In Jeong, Min Ju Kang, Nam Hoon Kim, Hyo Jong Kim, Sung-Gil Chi

Research output: Contribution to journalArticle

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Abstract

Caveolin-1 (CAV1) acts as a growth suppressor in various human malignancies, but its expression is elevated in many advanced cancers, suggesting the oncogenic switch of its role during tumor progression. To understand the molecular basis for the growth-promoting function of CAV1, we characterized its expression status, differential roles for tumor growth, and effect on glucose metabolism in colorectal cancers. Abnormal elevation of CAV1 was detected in a substantial fraction of primary tumors and cell lines and tightly correlated with promoter CpG sites hypomethylation. Depletion of elevated CAV1 led to AMPK activation followed by a p53-dependent G1 cell-cycle arrest and autophagy, suggesting that elevated CAV1 may contribute to ATP generation. Furthermore, CAV1 depletion downregulated glucose uptake, lactate accumulation, and intracellular ATP level, supporting that aerobic glycolysis is enhanced by CAV1. Consistently, CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. Ectopic expression of HMGA1 increased glucose uptake, whereas its knockdown caused AMPK activation. In addition, GLUT3 expression was strongly induced by cotransfection of CAV1 and HMGA1, and its overexpression was observed predominantly in tumors harboring high levels of CAV1 and HMGA1. Together, these data show that elevated CAV1 upregulates glucose uptake and ATP production through HMGA1-mediated GLUT3 transcription, suggesting that CAV1 may render tumor cells growth advantages by enhancing aerobic glycolysis.

Original languageEnglish
Pages (from-to)4097-4109
Number of pages13
JournalCancer Research
Volume72
Issue number16
DOIs
Publication statusPublished - 2012 Aug 15

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Caveolin 1
Glycolysis
Colorectal Neoplasms
Glucose
Neoplasms
AMP-Activated Protein Kinases
Adenosine Triphosphate
Growth
G1 Phase Cell Cycle Checkpoints
Autophagy
Tumor Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription. / Ha, Tae Kyu; Her, Nam Gu; Lee, Min Goo; Ryu, Byung Kyu; Lee, Jin Hee; Han, Jikhyon; Jeong, Seong In; Kang, Min Ju; Kim, Nam Hoon; Kim, Hyo Jong; Chi, Sung-Gil.

In: Cancer Research, Vol. 72, No. 16, 15.08.2012, p. 4097-4109.

Research output: Contribution to journalArticle

Ha, TK, Her, NG, Lee, MG, Ryu, BK, Lee, JH, Han, J, Jeong, SI, Kang, MJ, Kim, NH, Kim, HJ & Chi, S-G 2012, 'Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription', Cancer Research, vol. 72, no. 16, pp. 4097-4109. https://doi.org/10.1158/0008-5472.CAN-12-0448
Ha, Tae Kyu ; Her, Nam Gu ; Lee, Min Goo ; Ryu, Byung Kyu ; Lee, Jin Hee ; Han, Jikhyon ; Jeong, Seong In ; Kang, Min Ju ; Kim, Nam Hoon ; Kim, Hyo Jong ; Chi, Sung-Gil. / Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription. In: Cancer Research. 2012 ; Vol. 72, No. 16. pp. 4097-4109.
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AU - Lee, Jin Hee

AU - Han, Jikhyon

AU - Jeong, Seong In

AU - Kang, Min Ju

AU - Kim, Nam Hoon

AU - Kim, Hyo Jong

AU - Chi, Sung-Gil

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AB - Caveolin-1 (CAV1) acts as a growth suppressor in various human malignancies, but its expression is elevated in many advanced cancers, suggesting the oncogenic switch of its role during tumor progression. To understand the molecular basis for the growth-promoting function of CAV1, we characterized its expression status, differential roles for tumor growth, and effect on glucose metabolism in colorectal cancers. Abnormal elevation of CAV1 was detected in a substantial fraction of primary tumors and cell lines and tightly correlated with promoter CpG sites hypomethylation. Depletion of elevated CAV1 led to AMPK activation followed by a p53-dependent G1 cell-cycle arrest and autophagy, suggesting that elevated CAV1 may contribute to ATP generation. Furthermore, CAV1 depletion downregulated glucose uptake, lactate accumulation, and intracellular ATP level, supporting that aerobic glycolysis is enhanced by CAV1. Consistently, CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. Ectopic expression of HMGA1 increased glucose uptake, whereas its knockdown caused AMPK activation. In addition, GLUT3 expression was strongly induced by cotransfection of CAV1 and HMGA1, and its overexpression was observed predominantly in tumors harboring high levels of CAV1 and HMGA1. Together, these data show that elevated CAV1 upregulates glucose uptake and ATP production through HMGA1-mediated GLUT3 transcription, suggesting that CAV1 may render tumor cells growth advantages by enhancing aerobic glycolysis.

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