NUCKS1, a gene targeted by miR-497-5p, suppresses the antitumor effect of Brusatol and enhances malignancy of HNSCC via upregulating S100A9 expression

Brusatol (Bru), an extract derived from the Chinese medicinal plant Brucea javanica, exhibits a variety of antitumor effects. However, the precise role and regulatory mechanisms of Brusatol in head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we demonstrated that Brusatol promotes HNSCC cell death and inhibits cell growth and tumorigenesis both in vitro and in vivo. Mechanistically, Brusatol reduces the expression of Nuclear Ubiquitous Casein and Cyclin-Dependent Kinase Substrate 1 (NUCKS1). Elevated levels of NUCKS1 suppress Brusatol-induced cell death, whereas depletion of NUCKS1 enhances the antitumor effects of Brusatol. Additionally, NUCKS1 is significantly upregulated in HNSCC tissues, and its inhibition markedly reduces cell growth and tumorigenesis. Further investigations revealed that NUCKS1 ablation decreases the expression of S100 Calcium-Binding Protein A9 (S100A9). NUCKS1 enhances the activity of the S100A9 promoter and facilitates its transcription. Furthermore, our data indicate that miR-497-5p is upregulated in response to Brusatol treatment, which subsequently binds to the 3′UTR of NUCKS1 and downregulates its expression in HNSCC. Collectively, these findings highlight the critical role and regulatory mechanisms of NUCKS1 in HNSCC, suggesting that NUCKS1 antagonizes the antitumor effects of Brusatol and exacerbates the malignancy of HNSCC cells via transcriptional upregulation of S100A9.