SAM pointed domain containing E26 transformation-specific
transcription factor (SPDEF) plays dual roles in the initiation and development of human
malignancies. However, the
biological role of SPDEF in
head and neck squamous cell carcinoma (
HNSCC) remains unclear. In this study, the expression level of SPDEF and its correlation with the clinical parameters of patients with
HNSCC were determined using TCGA-HNSC, GSE65858, and our own clinical cohorts. CCK8, colony formation, cell cycle analysis, and a xenograft
tumor growth model were used to determine the molecular functions of SPDEF in
HNSCC. ChIP-qPCR, dual
luciferase reporter assay, and rescue experiments were conducted to explore the potential molecular mechanism of SPDEF in
HNSCC. Compared with normal epithelial tissues, SPDEF was significantly downregulated in
HNSCC tissues. Patients with
HNSCC with low SPDEF
mRNA levels exhibited poor clinical outcomes. Restoring SPDEF inhibited
HNSCC cell viability and colony formation and induced G0/G1 cell cycle arrest, while silencing SPDEF promoted cell proliferation in vitro. The xenograft
tumor growth model showed that
tumors with SPDEF overexpression had slower growth rates, smaller volumes, and lower weights. SPDEF could directly bind to the promoter region of NR4A1 and promoted its transcription, inducing the suppression of AKT, MAPK, and NF-κB signaling pathways. Moreover, silencing NR4A1 blocked the suppressive effect of SPDEF in
HNSCC cells. Here, we demonstrate that SPDEF acts as a
tumor suppressor by transcriptionally activating NR4A1 in
HNSCC. Our findings provide novel insights into the molecular mechanism of SPDEF in
tumorigenesis and a novel potential therapeutic target for
HNSCC.