CircENO1 drives gastric cancer progression via SPI1-mediated transcriptional activation of ENO1.
Abstract
Background
Circular RNAs (circRNAs) are critical regulators of tumor biology. However, the role of circENO1 in gastric cancer (GC) remains unclear. This study investigated the biological function and molecular mechanism of circENO1 in GC.
Methods
CircENO1 expression was evaluated using a publicly available dataset, clinical GC samples, and GC cell lines. Gain- and loss-of-function experiments, together with CCK-8, EdU incorporation, Transwell migration/invasion, EMT-associated marker, and glycolysis assays, were used to assess its biological functions. CHIRP, ChIP-qPCR, RIP, RNA pull-down, RNA-EMSA, FISH-IF, rescue, and epistasis experiments were used to investigate the circENO1-SPI1-ENO1 regulatory mechanism. Xenograft and metastasis models were used to assess circENO1 function in vivo.
Results
CircENO1 was significantly upregulated in GC tissues and cell lines, and higher circENO1 expression was associated with poorer prognosis and aggressive clinicopathological features. CircENO1 knockdown suppressed proliferation, migration, invasion, EMT-associated changes, and glycolytic activity, whereas circENO1 overexpression promoted malignant phenotypes. ENO1 overexpression reversed the inhibitory effects of circENO1 silencing. Mechanistically, circENO1 physically interacted with SPI1 and modulated its subcellular distribution. CircENO1 silencing reduced SPI1 enrichment, H3K27Ac, RNA polymerase II occupancy, and chromatin accessibility at the ENO1 promoter. CircENO1 overexpression increased H3K27Ac and RNA polymerase II occupancy, whereas SPI1 depletion abolished these effects. SPI1 overexpression partially restored ENO1 expression following circENO1 silencing. In vivo, circENO1 silencing suppressed tumor growth and metastatic burden.
Conclusions
These findings support a circENO1-SPI1-ENO1 regulatory axis linking malignant phenotypes and glycolytic activity in GC. Further clinical and preclinical validation is required to establish its broader biological and translational relevance.