LncRNA YIYA enhances pancreatic cancer proliferation under high-glucose conditions through RAS and PKM2 mediated metabolic reprogramming that reinforces the Warburg phenotype

Abstract

Diabetes and the resulting hyperglycemia are metabolic complications frequently linked to pancreatic cancer (PC). In this study, we observe that the long non-coding RNA (lncRNA)-YIYA, which resides in a genomic region (1q32), frequently altered in various cancers, is overexpressed under conditions of chronic or intermittent high glucose (HG; 25 mM) compared to normal glucose (NG; 5.5 mM) in pancreatic ductal adenocarcinoma (PDAC) cells. It plays a pivotal role in regulating cellular metabolism-linked proliferation of PDAC cells, both under 2D and 3D conditions. Analysis of clinical datasets suggested that patients with elevated YIYA expression generally experience reduced survival in pancreatic cancer. Mechanistically, YIYA was found to regulate cellular energy metabolism and promote a Warburg phenotype, thereby facilitating the rapid proliferative status of PDAC cells. YIYA-mediated effects were found to be dependent on KRAS. Interestingly, the RIP assay revealed that YIYA interacts not only with KRAS but also with an important enzyme catalyzing the final step of the biochemical process, glycolysis, pyruvate kinase M2 (PKM2). YIYA was found to be predominantly localised in the cytoplasm, protecting the stability of the KRAS protein under a hyperglycaemic state. Importantly, YIYA knockdown enhanced autophagy-mediated degradation of KRAS. Our study is the first to identify YIYA as a glucose-responsive lncRNA in PDAC cells, and to reveal a novel YIYA-mediated connection between oncogenic KRAS signalling and metabolic reprogramming. Targeting YIYA represents a promising therapeutic strategy by disrupting the KRAS-PKM2-Warburg axis, thereby sensitizing PDAC cells. Graphical abstracts figure: Proposed model illustrating the effect of hyperglycemia on lncRNA YIYA-mediated regulation of KRAS signaling and metabolic reprogramming in pancreatic cancerUnder hyperglycemic conditions, elevated glucose uptake through GLUT (Glucose Transporter) enhances glycolytic flux, leading to increased levels of PEP (Phosphoenolpyruvate) and activation of PKM2 (Pyruvate Kinase M2), which results in increased pyruvate flux toward the LDH (Lactate Dehydrogenase) pathway and subsequent increased lactate production, promoting the Warburg effect. Downregulation of MPC (Mitochondrial Pyruvate Carrier) also supports reduced shuttling of pyruvate towards the TCA (Tricarboxylic Acid) cycle. On the other hand, constitutively activated master regulator KRAS activates the downstream proliferative signalling via AKT and other DTs (Downstream targets), which upregulates various genes, including lncRNA YIYA aka LINC00538. YIYA exists in a functional complex with KRAS and PKM2, further reinforcing glycolytic and proliferative signalling. Additionally, YIYA suppresses autophagy-mediated degradation of KRAS. Together, these events contribute to hyperglycemia-driven epigenetic changes, metabolic reprogramming, and tumor progression in pancreatic cancer cells. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/685546v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@13d271org.highwire.dtl.DTLVardef@15d01fcorg.highwire.dtl.DTLVardef@12d7225org.highwire.dtl.DTLVardef@a11c5e_HPS_FORMAT_FIGEXP M_FIG C_FIG