The tumor suppressor gene lkb1 is essential for glucose homeostasis during zebrafish early development.
The liver kinase B1 (LKB1) is encoded by tumor suppressor gene STK11, which is mutated in Peutz-Jeghers syndrome patients. Lkb1 plays indispensable roles in energy homeostasis. However, how Lkb1 regulates energy homeostasis in vivo remains to be fully understood. We found that inactivation of zebrafish Lkb1 upregulates pyruvate dehydrogenase kinase 2 expression and inactivates pyruvate dehydrogenase complex by increasing phosphorylation of pyruvate dehydrogenase. As a result, glycolysis is significantly enhanced as indicated by increased lactate production, which resembles the Warburg effect in cancer cells. Inhibition of Pdk2 in lkb1 mutants with dichloroacetate, a promising anticancer drug, rescued the lactate production to wild-type level, suggesting the lkb1 mutant may be used to screen compounds targeting aerobic glycolysis in cancer therapy.
State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.|State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Xia
X
Kuang
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Chao
C
Liu
State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.|State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Junshun
J
Fang
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Weirui
W
Ma
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Jian
J
Zhang
State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
Sheng
S
Cui
D000818:Animals; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D025521:Tumor Suppressor Proteins; D029961:Zebrafish Proteins; D017346:Protein Serine-Threonine Kinases; D005947:Glucose
Lkb1; early development; gluconeogenesis; glycolysis; zebrafish