Abstract
BackgroundGlycolysis is a pivotal process in metabolic reprogramming of tumorigenesis. Previous research has indicated that lncRNAs might play crucial roles in glycolysis of various tumors. However, the function of lncRNAs in glycolysis of pancreatic cancer has not been fully elucidated.MethodsBio-information analyses were applied to reveal the potential glycolysis-associated lncRNA. RT-PCR and fluorescence in situ hybridization (FISH) assays were applied to detect the expression of antisense RNA1 of DICER1 (DICER1-AS1) in pancreatic cancer tissues and cell lines. Gain- and loss-of-function experiments were performed to evaluate the roles of DICER1-AS1 in glycolysis and tumorigenesis of PC. Mechanistic experiments including luciferase reporter assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) were employed to uncover the downstream targets and regulatory mechanism of DICER1-AS1 in glycolysis of PC.ResultsBio-information analysis indicated that DICER1-AS1 was downregulated in PC and negatively correlated with glycolytic genes expression. Meanwhile, overexpression of DICER1-AS1 inhibited glycolysis, proliferation, and metastasis of PC cells both in vitro and in vivo. Mechanistically, DICER1-AS1 promoted transcription of its sense gene DICER1 by recruiting transcriptional factor YY1 to the DICER1 promoter. Meanwhile, DICER1 promoted maturation of miR-5586-5p which consequently inhibited glycolytic gene expression including LDHA, HK2, PGK1, and SLC2A1. Notably, enhanced interaction between N6-methyladenosine (m6A) reader YTHDF3 and DICER1-AS1 led to degradation of DICER1-AS1 in response to glucose depletion. Moreover, our data revealed that YTHDF3 was a critical target for miR-5586-5p, by which forming a negative feedback with DICER1-AS1 to regulate glycolysis of PC.ConclusionOur results implicate a negative feedback of m6A reader YTHDF3 and glycolytic lncRNA DICER1-AS1 is involved in glycolysis and tumorigenesis of PC.
Highlights
Glycolysis is a pivotal process in metabolic reprogramming of tumorigenesis
DICER1‐AS1 is downregulated in pancreatic cancer tissues and negatively correlated with glycolysis pathway To explore the potential glycolysis-correlated Long noncoding RNAs (lncRNAs) in pancreatic cancer, we first analyzed the public dataset of pancreatic adenocarcinoma (PAAD) derived from The Cancer Genome Atlas (TCGA) database [12]
We identified 7 lncRNAs that were differentially expressed in pancreatic cancer (PC) patients based on the varied clinical progression, and negatively associated with the glycolysis pathway by the analysis from the gene set enrichment analysis (GSEA) [13] (Fig. 1A-B, Additional file 3: Figure S1A)
Summary
Glycolysis is a pivotal process in metabolic reprogramming of tumorigenesis. Previous research has indicated that lncRNAs might play crucial roles in glycolysis of various tumors. The function of lncRNAs in glycolysis of pancreatic cancer has not been fully elucidated. To maintain the urgent demand for tumorigenesis and aggressiveness, pancreatic cancer cells have extensively reprogrammed energy metabolism [1]. Glycolysis displays a less efficient metabolism with more lactate production, lower extracellular pH value, and more glucose consumption, even under an oxygen-enriched microenvironment [2]. Thereby, targeting the Warburg effect has been regarded as a promising therapeutic direction in tumors. Inhibitors of SLC2A1 or LDHA in combination with tumor chemotherapeutics displayed significant synergistic antitumor effect in vitro, which highlighting the promising role for cancer therapeutic strategy of glycolysis [5, 6]. The metabolic process and molecular mechanisms of glycolysis in PC progression remain uncertain and need to be further determined
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