A reciprocal feedback between N6-methyladenosine reader YTHDF3 and lncRNA DICER1-AS1 promotes glycolysis of pancreatic cancer through inhibiting maturation of miR-5586-5p

Abstract

Background 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. However, the function of lncRNAs in glycolysis of pancreatic cancer has not been fully elucidated. Methods Bio-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. Results Bio-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. Conclusion Our results implicate a negative feedback of m6A reader YTHDF3 and glycolytic lncRNA DICER1-AS1 is involved in glycolysis and tumorigenesis of PC.

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…The cellular response to such complex microenvironmental changes is regulated by multiple mechanisms. m 6 A methylation in TME leads to increased glycolysis and reduced mitochondrial function, thereby shifting energy production from mitochondria to glycolytic sources [ 55 ]. Interestingly, preferential activation of hypoxia-responsive glycolytic genes can be achieved via binding to m 6 A methylation regulators.…”

m1A Regulator ALKBH1 and TRMT10B as Potential Prognostic Biomarkers and Related to Tumor Immune Microenvironment in Pancreatic Adenocarcinoma

“…By binding to m6Amodi ed EIF3C mRNA, YTHDF1 ampli es the translation of EIF3C in an m6A-dependent manner thereby facilitating tumorigenesis and metastasis of ovarian cancer (Liu, Wei et al 2020). The negative feedback of YTHDF3 and glycolytic lncRNA DICER1-AS1 also participated in the tumorigenesis of PAAD (Hu, Tang et al 2022). To further explore the correlation between the speci c m1A regulators and the prognosis of PAAD, we got Kaplan-Meier plots using OncoLnc database.…”

M1A regulator ALKBH1 and TRMT10B as potential prognostic bio markers and related to the tumor immune microenvironment in pan creatic adenocarcinoma

“…By binding to m6A-modi ed EIF3C mRNA, YTHDF1 ampli es the translation of EIF3C in an m6A-dependent manner thereby facilitating tumorigenesis and metastasis of ovarian cancer(38). The negative feedback of YTHDF3 and glycolytic lncRNA DICER1-AS1 also participated in the tumorigenesis of PAAD (39). To further explore the correlation between the speci c m1A regulators and the prognosis of PAAD, we got Kaplan-Meier plots using OncoLnc database.…”