Long Noncoding RNA MALAT1 regulates cancer glucose metabolism by enhancing mTOR-mediated TCF7L2 translation.

Reprogrammed glucose metabolism of enhanced aerobic glycolysis or the “Warburg effect”, has been identified as a hallmark of cancer. Many oncogenes and tumor suppressors affect cancer metabolism by regulating the expression of metabolic enzymes, although in many cases the underlying molecular mechanisms are unknown. The roles of long noncoding RNAs (lncRNAs) in regulating cancer metabolism at the level of both glycolysis and gluconeogenesis are mostly undiscovered. 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 overexpression increased glycolysis by regulating the expression of key metabolic glycolytic genes. Transient knockdown of MALAT1 in HCC cells resulted in increased gluconeogenesis and expression of G6PC and PCK1, rate limiting enzymes of gluconeogenesis. We found that MALAT1 up-regulates the expression of glycolytic genes and down-regulate gluconeogenic enzymes by enhancing the translation of the metabolic transcription factor TCF7L2. MALAT1- enhanced TCF7L2 translation was mediated by the mTORC1-4EBP1 axis, as pharmacological or genetic inhibition of mTOR or Raptor resulted in decreased expression of TCF7L2. Furthermore, expression of a hypophosphorylated mutant version of eIF4E Binding protein (4EBP1) resulted in decreased expression of TCF7L2. Knockdown of TCF7L2 in MALAT1 overexpressing cells and HCC cell lines abolished their tumorogenic potential suggesting that MALAT1 effects 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.