Long noncoding RNA MALAT1 regulates cancer glucose metabolism by enhancing mTOR-Mediated Translation of TCF7L2

Pushkar Malakar, Ilan Stein, Amijai Saragovi, Roni Winkler, Noam Stern-Ginossar, Michael Berger, Eli Pikarsky, Rotem Karni*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

131 Scopus citations

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 50-untranslated region (UTR), as determined by polysome fractionation and 50UTR-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. Significance: These findings show that lncRNA MALAT1 contributes to HCC development by regulating cancer glucose metabolism, enhancing glycolysis, and inhibiting gluconeogenesis via elevated translation of the transcription factor TCF7L2.

Original languageAmerican English
Pages (from-to)2480-2493
Number of pages14
JournalCancer Research
Volume79
Issue number10
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
The authors wish to thank Dr. Zahava Siegfried for comments on the article and Fatima Gebauer (CRG, Barcelona) for the pSG5 Luc Plasmid. This study was supported in part by Israel Science Foundation (ISF; ISF Grant no. 1290/12 to R. Karni).

Publisher Copyright:
© 2019 American Association for Cancer Research.

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