Nuclear factor of activated T cells (NFATc1-c4), a family of
transcription factors, is involved in many biological processes by regulating various downstream target genes. However, their role in
cancer progression remains controversial. We here report that
NFATc3 is the dominant
isoform of NFAT in human oral epithelial cells, and its expression was increased in a stepwise manner during the progression of oral/
oropharyngeal squamous cell carcinoma (OSCC). More importantly,
NFATc3 was highly enriched in self-renewing
cancer stem-like cells (CSCs) of OSCC. Increased expression of
NFATc3 was required for the maintenance of CSC self-renewal, as
NFATc3 inhibition suppressed
tumor sphere formation in OSCC cells. Conversely, ectopic
NFATc3 expression in non-tumorigenic immortalized oral epithelial cells resulted in the acquisition of self-renewal and increase in CSC phenotype, such as enhanced ALDH1HIGH cell population, mobility and drug resistance, indicating the functional role of
NFATc3 in the maintenance of CSC phenotype.
NFATc3 expression also converted the non-tumorigenic oral epithelial cells to malignant phenotypes. Mechanistic investigations further reveal that
NFATc3 binds to the promoter of OCT4, a stemness
transcription factor, for its activation, thereby promoting CSC phenotype. Moreover, suppression of OCT4 abrogated CSC phenotype in the cell with ectopic
NFATc3 overexpression and OSCC, and ectopic OCT4 expression sufficiently induced CSC phenotype. Our study indicates that
NFATc3 plays an important role in the maintenance of
cancer stemness and OSCC progression via novel NFATc3-OCT4 axis, suggesting that this axis may be a potential therapeutic target for OSCC CSCs.