Transcriptional Activation of SKA3 by SOX9 Promotes the Malignant Progression of Laryngeal Squamous Cell Carcinoma by Regulating AKR1C1

Laryngeal squamous cell carcinoma (LSCC) is one of the most common types of head and neck cancer, posing a significant threat to public health. The spindle and kinetochore-associated complex subunit 3 (SKA3), a microtubule-binding subcomplex of the outer kinetochore, participates in cancer progression. However, its role in the progression of LSCC remains unclear. This study aimed to investigate the regulatory effects of SKA3 on LSCC progression and its underlying mechanism. In this study, the expression levels of SKA3 and aldo-keto reductase family 1 member C1 (AKR1C1) mRNA were assessed by quantitative real-time PCR. Protein expression was evaluated using western blotting. Cell proliferation was analyzed using the cell counting kit-8 assay, while apoptosis was assessed by flow cytometry. Cell migration and invasion were measured via Transwell assays. The levels of Fe2+ and glutathione were analyzed with colorimetric assays, while reactive oxygen species (ROS) levels were determined by flow cytometry. Chromatin immunoprecipitation and dual-luciferase reporter assays were employed to explore the interaction between SOX9 and SKA3. The impact of SKA3 silencing and AKR1C1 overexpression on tumor formation was investigated using a xenograft mouse model. The results showed that SKA3 expression was elevated in LSCC tissues and cells when compared with corresponding normal tissues and human nasopharyngeal epithelial cells. Silencing SKA3 suppressed LSCC cell proliferation, migration, and invasion, while promoting apoptosis and ferroptosis. SKA3 upregulated AKR1C1, a key ferroptosis-related gene, in TU177 and AMC-HN-8 cells. Overexpression of AKR1C1 mitigated the effects of SKA3 silencing on the malignant phenotypes of these cells. SOX9 was identified as a transcriptional activator of SKA3 in TU177 and AMC-HN-8 cells, and AKR1C1 overexpression reversed the inhibitory effect of SKA3 silencing on tumor growth in vivo. Thus, SKA3 played a pivotal role in the progression of LSCC through the SOX9/SKA3/AKR1C1 axis, suggesting that targeting SKA3 might have significant clinical implications for the treatment of LSCC.