| Popis: |
KRAS-driven metabolic reprogramming is one of the key features of pancreatic ductal adenocarcinoma (PDAC) cells; however, the metabolic roles of other oncogenic genes, such as YY1, in PDAC development are still unclear. In this study, we observed that YY1 expression was significantly elevated in human PDAC tissues and was positively correlated with a poor disease progression. Further, in vitro studies confirmed that YY1 deletion inhibited PDAC cell proliferation and tumorigenicity. Moreover, YY1 deletion also led to impaired mitochondrial RNA expression, which further induced mitochondrial oxidative phosphorylation (OXPHOS) complex assembly deficiency and altered cellular nucleotide homeostasis. Mechanistically, the impairment of mitochondrial OXPHOS function lowered the generation of aspartate, an output of the tricarboxylic acid cycle (TCA) and resulted in the inhibition of cell proliferation, owing to the absence of aspartate-associated nucleotide availability. Conversely, exogenous supplementation with aspartate fully restored PDAC cell proliferation. Altogether, our findings suggested that YY1 promotes PDAC cell proliferation by enhancing mitochondrial respiration and the TCA, which favors aspartate-associated nucleotide synthesis. These findings indicate that targeting nucleotide biosynthesis is a promising strategy for PDAC treatment. |
