Abstract
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.
Highlights
A large body of evidence indicates that human cancer can be categorized as a stem cell disease[1]
We found that Sex-determining region Y-box2 (SOX2) promotes chemoresistance, confers Cancer stem cells (CSCs) properties, and promotes epithelial–mesenchymal transition (EMT) in colorectal cancer (CRC)[5]
Gene set enrichment analysis (GSEA) indicated that there was a positive correlation between SOX2 high expression and ABC transporters signatures (TCGA, n = 465, Supplementary Fig. S1A). Quantitative real-time PCR (qRT-PCR) and western blot revealed that ABCC2 was markedly elevated in SW620 cells than that in SW480 cells (Fig. 1A)
Summary
A large body of evidence indicates that human cancer can be categorized as a stem cell disease[1]. Cancer stem cells (CSCs) represent a minor subpopulation of the tumor bulk that exhibits self-renewal capacity, induces. Zhu et al Cell Death and Disease (2021)12:449 molecular mechanism may help identify novel diagnostic biomarkers and facilitate the development of effective therapeutic interventions against CRC. Several ABC transporters, including ABCB1, ABCC2, ABCG2, and ABCB5, have been identified in CSCs-driven chemoresistance[10,11,12,13]. SOX2 has been implicated in the acquisition of chemoresistance by upregulating the expression of ABC transporters in glioma cells and gastric cancer cells[14,15]. The role of ABC transporters in SOX2-induced chemoresistance is poorly understood in CRC
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