Long Noncoding RNA MALAT1 Regulates Cancer Glucose Metabolism by Enhancing mTOR-Mediated Translation of TCF7L2
- 15 May 2019
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 79 (10), 2480-2493
- https://doi.org/10.1158/0008-5472.can-18-1432
Abstract
Reprogrammed glucose metabolism of enhanced aerobic glycolysis (or the Warburg effect) is known as a hallmark of cancer. The roles of long noncoding RNAs (lncRNA) in regulating cancer metabolism at the level of both glycolysis and gluconeogenesis are mostly unknown. We previously showed that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acts as a proto-oncogene in hepatocellular carcinoma (HCC). Here we investigated the role of MALAT1 in regulating cancer glucose metabolism. MALAT1 upregulated the expression of glycolytic genes and downregulated gluconeogenic enzymes by enhancing the translation of the metabolic transcription factor TCF7L2. MALAT1-enhanced TCF7L2 translation was mediated by upregulation of SRSF1 and activation of the mTORC1-4EBP1 axis. Pharmacological or genetic inhibition of mTOR and Raptor or expression of a hypophosphorylated mutant version of eIF4E binding protein (4EBP1) resulted in decreased expression of TCF7L2. MALAT1 expression regulated TCF7L2 mRNA association with heavy polysomes, probably through the TCF7L2 5'UTR as determined by polysome fractionation and 5'UTR-reporter assays. Knockdown of TCF7L2 in MALAT1-overexpressing cells and HCC cell lines affected their metabolism and abolished their tumorigenic potential, suggesting that the effects of MALAT1 on glucose metabolism are essential for its oncogenic activity. Taken together, our findings suggest that MALAT1 contributes to HCC development and tumor progression by reprogramming tumor glucose metabolism.Keywords
Other Versions
Funding Information
- ISF (1290/12)
This publication has 55 references indexed in Scilit:
- Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYBPLoS Genetics, 2013
- TCF7L2 Modulates Glucose Homeostasis by Regulating CREB- and FoxO1-Dependent Transcriptional Pathway in the LiverPLoS Genetics, 2012
- mTOR Signaling in Growth Control and DiseaseCell, 2012
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Long Intergenic Noncoding RNAs: New Links in Cancer ProgressionCancer Research, 2011
- Genetic Dissection of the Oncogenic mTOR Pathway Reveals Druggable Addiction to Translational Control via 4EBP-eIF4ECancer Cell, 2010
- MYC-Induced Cancer Cell Energy Metabolism and Therapeutic OpportunitiesClinical Cancer Research, 2009
- The splicing-factor oncoprotein SF2/ASF activates mTORC1Proceedings of the National Academy of Sciences of the United States of America, 2008
- Identification and Validation of Oncogenes in Liver Cancer Using an Integrative Oncogenomic ApproachCell, 2006
- Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetesNature Genetics, 2006