Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription.
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.
School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Tae-Kyu
TK
Ha
Nam-Gu
NG
Her
Min-Goo
MG
Lee
Byung-Kyu
BK
Ryu
Jin-Hee
JH
Lee
Jikhyon
J
Han
Seong-In
SI
Jeong
Min-Ju
MJ
Kang
Nam-Hoon
NH
Kim
Hyo-Jong
HJ
Kim
Sung-Gil
SG
Chi
D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000332:Aerobiosis; D000818:Animals; D001343:Autophagy / Q000502:physiology; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D005947:Glucose / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000096:biosynthesis* / Q000235:genetics; D006019:Glycolysis; D045325:HCT116 Cells; D025741:HMGA1a Protein / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
C495540:CAV1 protein, human; D051242:Caveolin 1; D051274:Glucose Transporter Type 3; C495687:SLC2A3 protein, human; D016159:Tumor Suppressor Protein p53; D025741:HMGA1a Protein; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D005947:Glucose