Wnt/Snail signaling regulates cytochrome C oxidase and glucose metabolism.
Wnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. The pathway also induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we show that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. We found that Wnt induced a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. In addition, Wnt-induced mitochondrial repression and glycolytic switching occurred through the canonical β-catenin/T-cell factor 4/Snail pathway. Short hairpin RNA-mediated knockdown of E-cadherin, a regulator of EMT, repressed mitochondrial respiration and induced a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism. Together, our findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression.
Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan, Korea.
Su Yeon
SY
Lee
Hyun Min
HM
Jeon
Min Kyung
MK
Ju
Cho Hee
CH
Kim
Gyesoon
G
Yoon
Song Iy
SI
Han
Hye Gyeong
HG
Park
Ho Sung
HS
Kang
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003576:Electron Transport Complex IV / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D003576:Electron Transport Complex IV; D005947:Glucose