The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells.

Abstract

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.

• Authors: Fei Luo, Xinlu Liu, Min Ling, Lu Lu, Le Shi, Xiaolin Lu, Jun Li, Aihua Zhang, Qizhan Liu
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1862 Issue 9 Pg. 1685-95 (09 2016) ISSN: 0006-3002 [Print] Netherlands
• PMID: 27287256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Arsenites
• Basic Helix-Loop-Helix Transcription Factors
• Carcinogens
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• MALAT1 long non-coding RNA, human
• RNA, Long Noncoding
• endothelial PAS domain-containing protein 1
• Lactic Acid
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human
• Glucose
• arsenite

Topics

• Arsenites (toxicity)
• Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Carcinogens (toxicity)
• Cell Line
• Gene Knockdown Techniques
• Glucose (metabolism)
• Glycolysis (drug effects, genetics, physiology)
• Hepatocytes (drug effects, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Lactic Acid (metabolism)
• Models, Biological
• Protein Stability
• RNA Interference
• RNA, Long Noncoding (antagonists & inhibitors, genetics, metabolism)
• Von Hippel-Lindau Tumor Suppressor Protein (metabolism)