Sex-determining region Y-box2 (SOX2), a master regulator of embryonic and induced pluripotent stem cells, drives cancer stem cells (CSCs) properties, fuels tumor initiation, and contributes to tumor aggressiveness. Our previous study has demonstrated the oncogenic role of SOX2 in colorectal cancer (CRC). In this study, we sought to elucidate the underlying mechanisms. Cell function experiments were performed to detect chemoresistance, proliferation, stemness, migration, and invasion in vitro. Chromatin immunoprecipitation, co-immunoprecipitation, luciferase reporter assay, and immunofluorescence were performed to explore the regulation of ABCC2, β-catenin, and Beclin1 by SOX2. The carcinogenic role of SOX2-β-catenin/Beclin1-ABCC2 axis in vivo was analyzed by CRC tissues and xenograft models. Here, we reported that SOX2 sustained chemoresistance by transcriptional activation of ABCC2 expression. Suppressing either β-catenin or autophagy signaling curbed SOX2-driven chemoresistance, stemness, and epithelial–mesenchymal transition (EMT). Mechanistically, SOX2 combined with β-catenin and increased its nuclear expression and transcriptional activity. Transcriptional activation of Beclin1 expression by SOX2 consequently activating autophagy and inducing malignant phenotype. Furthermore, overexpression of β-catenin or Beclin1 facilitated ABCC2 expression. The clinical analyses showed that high expression of ABCC2 and Beclin1 were positively correlated with SOX2 and were associated with poor prognosis in CRC patients. Finally, xenograft models revealed that inhibition of SOX2 expression and autophagy restrained tumor growth and chemoresistance in vivo. Conclusively, we demonstrated a novel mechanism by which the SOX2-β-catenin/Beclin1/autophagy signaling axis regulates chemoresistance, stemness, and EMT in CRC. Our findings provide novel insights into CRC carcinogenesis and may help develop potential therapeutic candidates for CRC.

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.