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http://dx.doi.org/10.5352/JLS.2019.29.11.1179

High-mobility Group Box 1 Induces the Epithelial-mesenchymal Transition, Glycolytic Switch, and Mitochondrial Repression via Snail Activation  

Lee, Su Yeon (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Ju, Min Kyung (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Jeon, Hyun Min (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Kim, Cho Hee (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Park, Hye Gyeong (Nanobiotechnology Center, Pusan National University)
Kang, Ho Sung (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
Publication Information
Journal of Life Science / v.29, no.11, 2019 , pp. 1179-1191 More about this Journal
Abstract
Cancer cells undergo the epithelial-mesenchymal transition (EMT) and show unique oncogenic metabolic phenotypes such as the glycolytic switch (Warburg effect) which are important for tumor development and progression. The EMT is a critical process for tumor invasion and metastasis. High-mobility group box 1 (HMGB1) is a chromatin-associated nuclear protein, but it acts as a damage-associated molecular pattern molecule when released from dying cells and immune cells. HMGB1 induces the EMT, as well as invasion and metastasis, thereby contributing to tumor progression. Here, we show that HMGB1 induced the EMT by activating Snail. In addition, the HMGB1/Snail cascade was found induce a glycolytic switch. HMGB1 also suppressed mitochondrial respiration and cytochrome c oxidase (COX) activity by a Snail-dependent reduction in the expression of the COX subunits COXVIIa and COXVIIc. HMGB1 also upregulated the expression of several key glycolytic enzymes, including hexokinase 2 (HK2), phosphofructokinase-2/fructose-2,6-bisphosphatase 2 (PFKFB2), and phosphoglycerate mutase 1 (PGAM1), in a Snail-dependent manner. However, HMGB1 was found to regulate some other glycolytic enzymes including lactate dehydrogenases A and B (LDHA and LDHB), glucose transporter 1 (GLUT1), and monocarboxylate transporters 1 and 4 (MCT1 and 4) in a Snail-independent manner. Transfection with short hairpin RNAs against HK2, PFKFB2, and PGAM1 prevented the HMGB1-induced EMT, indicating that glycolysis is associated with HMGB1-induced EMT. These findings demonstrate that HMGB1 signaling induces the EMT, glycolytic switch, and mitochondrial repression via Snail activation.
Keywords
Epithelial-mesenchymal transition; glycolytic switch; HMGB1; snail;
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