Abstract
Autophagy is an essential catabolic process that orchestrates cellular homeostasis and plays dual roles in tumor promotion and suppression. However, the mechanism by which autophagy affects the self-renewal of cancer stem cells (CSCs) remains unclear. In this study, we investigated whether autophagy activation contributes to CSC properties of head and neck squamous cell carcinoma (HNSCC). The results showed that the autophagy level and CSC properties of HNSCC cells were elevated in response to several adverse conditions, including treatment with cisplatin, starvation, and hypoxia. Pretreatment with autophagy inhibitors, such as 3-MA and chloroquine, diminished the CSC properties acquired under adverse conditions. In addition, the isolated CSCs were endowed with stronger autophagic activity than non-CSCs, and the CSC properties were dampened when autophagy was inhibited either by 3-MA, chloroquine, or Beclin1 knockdown. Notably, the tumor-initiating activity of CSCs was decreased upon knocking down Beclin1. Further study revealed that FOXO3, a substrate for autophagy, was enriched in the nucleus of cells with lower autophagy levels. Nuclear FOXO3 directly bound to the promoter region of SOX2 and negatively regulated its transcriptional activity. Overexpression of FOXO3 decreased the expression of SOX2 and thereby impaired the CSC phenotype both in vitro and in vivo. Taken together, our findings suggest that the activation of autophagy is essential for the acquisition of CSC properties in adverse conditions and the self-renewal of CSCs. We clarify the role of autophagy in regulating the CSC phenotype and demonstrate that the noncanonical FOXO3/SOX2 axis is the intrinsic regulatory mechanism.
Highlights
Worldwide, head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, and over 600,000 new cases are reported annually [1]
Previous studies have reported that cisplatin, starvation, and These results indicated that cancer stem cells (CSCs) had a higher autophagy level hypoxia are closely related to the CSC properties of tumor cells than non-CSCs
We found that autophagy and stemness of HNSCC increased significantly when treated with cisplatin, starvation, and hypoxia, and the activation of autophagy was crucial for the acquisition of CSC properties
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, and over 600,000 new cases are reported annually [1]. Electron cell group grew more rapidly than those in the control group micrographs showed that the formation of autophagic vesicles (Supplementary Fig. 2J) These results demonstrated that the increased in tumor cells after treatment with cisplatin, starvation, isolated sphere cells in our experiment were CSCs. and hypoxia (Fig. 1D). To confirm whether the elevated autophagic flux of FOXO3 accounts for the enhanced CSC properties in adverse conditions, Beclin is a critical protein in the process of autophagy and is autophagy inhibitors 3-MA and chloroquine (CQ) were used in essential for the maintenance of cancer stem-like cells and our studies. We found that autophagy was inhibited in sphere cells after Beclin knockdown, accompanied by decreased expressions of CSC-related proteins, which demonstrated a crucial role of autophagy in the maintenance of CSC properties (Fig. 4A, B and Supplementary Fig. 4B). After Beclin knockdown, the sphere formation, colony formation, migration, and invasion abilities of sphere cells significantly decreased
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