NR4A1 has been reported to play critical roles in tumorigenesis by regulating several oncogenic signaling pathways, including acute myeloid leukemia, colorectal cancer, and oral squamous cell carcinoma.18,21,25 In acute myeloid leukemia, NR4A1/3-null hematopoietic stem cells showed elevated p-AKT and p-ERK1/2 levels and improved cell proliferation.20 Our results revealed that SPDEF suppressed p-AKT, p-GSK3β, and p-ERK1/2, demonstrating that SPDEF can inhibit several oncogenic signaling pathways by activating NR4A1 transcription. This evidence concerns the gene AKT1 and oral cavity squamous cell carcinoma.