SOX2 Promotes Vasculogenic Mimicry by Accelerating Glycolysis via the LncRNA AC005392.2-GLUT1 Axis in Colorectal Cancer

Abstract

Abstract Vasculogenic mimicry (VM), a new model of angiogenesis, fulfills the metabolic demands of solid tumors and contributes to tumor aggressiveness. Our previous study demonstrated the effect of SOX2 in promoting VM in colorectal cancer (CRC). In this study, we aimed to elucidate the underlying mechanisms behind this effect. The influence of SOX2 on glycolysis was examined via assessment of glucose consumption, lactate production, and extracellular acidification rate (ECAR). Candidate long non-coding RNA (lncRNA) was analyzed using lncRNA microarray. Chromatin immunoprecipitation, luciferase reporter assays, RNA pulldown, and mass spectrometry analyses were performed to demonstrate the detailed molecular mechanism of the SOX2-lncRNA AC005392.2-GLUT1 signaling axis. Here, we report that SOX2 overexpression enhanced glycolysis and sustained VM formation via the transcriptional activation of AC005392.2. Suppression of either AC005392.2 expression or glycolysis signaling curbed SOX2-driven VM formation in vivo and in vitro. Mechanistically, SOX2 combined with the promoter of AC005392.2, which decreased H3K27me3 enrichment and thus increased its transcriptional activity. Furthermore, overexpression of AC005392.2 increased the stability of GLUT1 protein by enhancing its SUMOylation, leading to a decrease in the ubiquitination and degradation of GLUT1. Additionally, overexpression of GLUT1 contributed to SOX2-mediated glycolysis and VM. Clinical analyses showed that increased levels of AC005392.2, GLUT1, and EPHA2 expression were positively correlated with SOX2 and were also associated with poor prognoses in patients with CRC. Our study conclusively demonstrates that the SOX2-lncRNA AC005392.2-GLUT1 signaling axis regulates VM formation in CRC, offering a foundation for the development of new antiangiogenic drugs or new drug combination regimens.