Toxicol Appl Pharmacol. 2026 Jan 02. pii: S0041-008X(26)00002-5. [Epub ahead of print]
117706
In this research, we mainly focus on the mechanism of histone deacetylase sirtuin 2 (SIRT2) affecting the growth and metastasis of tongue cancer using in vitro and in vivo experiments. Human tongue cancer cells SCC-25, SCC-9, CAL-27, CAL-33 and human oral epithelial cells were cultured for cell line selection. In vitro, SCC-25 cells were manipulated with pcDNA3.1-SIRT2, pcDNA3.1-FZD1, pcDNA3.1-NC, or/and Wnt/β-catenin pathway inhibitor (MSAB) or activator (SKL2001), while CAL-33 cells were treated with siRNA-SIRT2, siRNA-NC or MSAB. The levels of H3K27ac, β-catenin (nuclear, cytoplasmic and total protein), and Wnt1/3a/7a were detected using WB. Based on data from the ENCODE database, the enrichment level of H3K27ac in the FZD1 promoter region was examined by ChIP experiment. Finally, an orthotopic xenograft tumor model in nude mice was constructed for in vivo validation. Re-expression of SIRT2 impaired the proliferative, invasive, and migratory behaviors of tongue cancer cells, while strengthening their apoptosis. Furthermore, SIRT2 decreased H3K27 acetylation, resulting in increased cytoplasmic β-catenin and decreased expression of FZD1, Wnt1/3a/7a, and nuclear β-catenin. FZD1 overexpression or the Wnt/β-catenin pathway activation partially compromised the inhibitory impacts of SIRT2 on the aforementioned behaviors of human tongue cancer cells. The in vivo validation suggested that SIRT2 played a regulatory role in FZD1 expression and Wnt/β-catenin pathway, thereby hindering the growth and metastasis of the orthotopic tongue cancer xenograft model. SIRT2 inhibits the transcriptional expression of FZD1 through H3K27 deacetylation to block the Wnt/β-catenin pathway, consequently suppressing the growth and metastasis of tongue cancer.
Keywords: Frizzled-1; H3K27ac; Metastasis; Proliferation; Sirtuin 2; Tongue cancer; Wnt Pathway; β-Catenin