생명과학회지 (Journal of Life Science)

  • 제29권11호
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  • Pages.1179-1191
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  • 2019
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
권호 표지
DOI QR코드

DOI QR Code

HMGB1/Snail cascade에 의한 epithelial-mesenchymal transition 및 glycolytic switch, mitochondrial repression 유도

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

  • 이수연 (부산대학교 자연과학대학 분자생물학과) ;
  • 주민경 (부산대학교 자연과학대학 분자생물학과) ;
  • 전현민 (부산대학교 자연과학대학 분자생물학과) ;
  • 김초희 (부산대학교 자연과학대학 분자생물학과) ;
  • 박혜경 (부산대학교 한국나노바이오테크놀러지센터) ;
  • 강호성 (부산대학교 자연과학대학 분자생물학과)
  • 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)
  • 투고 : 2019.09.20
  • 심사 : 2019.11.07
  • 발행 : 2019.11.30
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초록

암세포는 epithelial mesenchymal transition (EMT)를 통해 tumor invasion과 metastasis가 일어나며, 또한 정상세포와 다른 oncogenic metabolic phenotypes 획득 즉, glycolytic switch 등이 암 발생과 진행에 깊이 연관되어 있음이 잘 알려져 있다. High-mobility group box 1 (HMGB1)은 chromatin-associated nuclear protein으로 알려져 있으나, dying cells 또는 immune cells로부터 방출되기도 한다. 방출된 HMGB1은 damage-associated molecular pattern (DAMP)로서 작용하여 EMT 및 invasion, metastasis를 유도함으로서 tumor progression에 기여한다고 알려졌다. 본 연구에서 HMGB1에 의해 EMT와 glycolytic switch 유도되며, 이 과정은 Snail 의존적임을 확인하였다. 또한 HMGB1/Snail cascade는 COX subunits인 COXVIIa와 COXVIIc의 발현 억제를 통해 mitochondrial repression과 cytochrome c oxidase (COX) inhibition을 유도하였다. HMGB1은 Snail를 통해 glycolytic switch의 주요 효소인 hexokinase 2 (HK2), phosphofructokinase-2/fructose-2,6-bisphosphatase 2 (PFKFB2), phosphoglycerate mutase 1 (PGAM1)의 발현을 증가시켰다. 이들 효소는 glycolytic switch에 중요하게 관여하는 것으로 알려져 있다. 이들 해당과정의 효소들을 knockdown한 결과 HMGB1에 의한 EMT를 억제함으로써 glycolysis와 HMGB1-induced EMT가 밀접하게 연관되어 있을 제시하였다. 이상의 연구 결과들은 HMGB1/Snail cascade가 EMT 및 glycolytic switch, mitochondrial repression에 중요하게 작용할 것임을 시사한다.

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.

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