The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells.
Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite, a well-established human carcinogen, is unknown. Long non-coding RNAs (lncRNAs) act as regulators in various cancers, but how lncRNAs regulate glucose metabolism remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases lactate production; glucose consumption; and expression of glycolysis-related genes, including HK-2, Eno-1, and Glut-4. In L-02 cells exposed to arsenite, the lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and hypoxia inducible factors (HIFs)-α, the transcriptional regulators of cellular response to hypoxia, are over-expressed. In addition, HIF-1α, not HIF-2α, is involved in arsenite-induced glycolysis, and MALAT1 enhances arsenite-induced glycolysis. Although MALAT1 regulates HIF-α and promotes arsenite-induced glycolysis, MALAT1 promotes glycolysis through HIF-1α, not HIF-2α. Moreover, arsenite-increased MALAT1 enhances the disassociation of Von Hippel-Lindau (VHL) tumor suppressor from HIF-1α, alleviating VHL-mediated ubiquitination of HIF-1α, which causes accumulation of HIF-1α. In sum, these findings indicate that MALAT1, acting through HIF-1α stabilization, is a mediator that enhances glycolysis induced by arsenite. These results provide a link between the induction of lncRNAs and the glycolysis in cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity.
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Fei
F
Luo
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Xinlu
X
Liu
Jiangsu Center for Disease Control and Prevention, Nanjing 210009, Jiangsu, People's Republic China.
Min
M
Ling
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Lu
L
Lu
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Le
L
Shi
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Xiaolin
X
Lu
The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang 550025, Guizhou, People's Republic of China.
Jun
J
Li
The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang 550025, Guizhou, People's Republic of China.
Aihua
A
Zhang
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China. Electronic address: drqzliu@hotmail.com.
Qizhan
Q
Liu
D018053:Arsenites / Q000633:toxicity*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008954:Models, Biological; D055550:Protein Stability; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D018053:Arsenites; D051792:Basic Helix-Loop-Helix Proteins; D002273:Carcinogens; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid; D062085:RNA, Long Noncoding; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C557041:MALAT1 long non-coding RNA, human; C497446:VHL protein, human; C015001:arsenite
Arsenite; Glycolysis; HIFs; lncRNAs