Supplementary Information: Figure S1: MALAT1 affects cancer glucose metabolism Figure S2: Glucose metabolism in HCC cell lines with MALAT1 knockdown. Figure S3: Regulation of TCF7L2 protein expression by MALAT1 in HCC cell lines. Figure S4: A non-phosphorylatable mutant of 4EBP1 inhibits TCF7L2 protein expression and expression of glycolytic genes. Figure S5: SRSF1 regulates TCF7L2 levels post-transcriptionally. Figure S6: TCF7L2 modulates glucose metabolism in a HCC cell line. Figure S7: MALAT1 and TCF7L2 regulate gluconeogenesis through the same pathway. Figure S8: Oncogenic properties of HCC cell lines with TCF7L2 knockdown. Figure S9: TCF7L2 protein, Gluconeogenesis and Glycolytic enzyme expression in livers from mouse HCC model Mdr2-/-. Table S1: List and sequences of shRNAs, siRNAs and PCR primers used in the paper
ARTICLE 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′-untranslated region (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.
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.