SKA1 promotes properties associated with tumor initiation and progression in OSCC and OLP

Global gene expression comparisons between OSCC and normal oral mucosa samples have been performed in more than 20 cohorts since 2004. Pathologically relevant genes (and associated pathways) are hypothesized to be deregulated in all studies. A bioinformatics analysis was performed to identify recurrently deregulated genes and pathways in OSCC compared to normal oral mucosa. Among the 629 consistently deregulated genes, genes related to mitosis and cell division were highly enriched. These included the gene spindle and kinetochore-associated complex subunit 1 (SKA1), which was consistently upregulated in OSCC and associated with poor survival of OSCC patients. SKA1 is part of the outer kinetochore and is required for proper chromosome segregation. An oncogenic role of SKA1 has been established in other solid tumor entities; however, its role in OSCC and in the transformation of premalignant cells to overt cancer cells has not been extensively studied. To investigate its role, SKA1 was overexpressed in the human OSCC cell line CAL-33 and the oral premalignant leukoplakia cell line MSK-Leuk1, and knocked down in the human OSCC cell line SCC-25. SKA1 promoted proliferation and 2D colony formation, and reduced the proportion of cells in metaphase by shortening the duration of this phase in OSCC cells. In addition, SKA1 promoted cell migration as assessed by the scratch assay. Growth and 3D colony formation in Matrigel® were enhanced by SKA1 expression. Its overexpression increased, and its knockdown decreased the radioresistance of OSCC cells, while resistance to chemotherapy drugs used in OSCC treatment remained unchanged. In the premalignant cell line MSK-Leuk1, SKA1 increased proliferation, 2D colony formation, migration, and 3D colony formation. RNA-sequencing of CAL-33 and MSK-Leuk1 cells overexpressing SKA1 and control cells showed that SKA1 promoted the activation of different signaling pathways in the two cell lines. In OSCC cells, EMT and inflammatory response-related pathways were enriched upon SKA1 overexpression, while in premalignant cells, genes associated with proliferation and with SKA1 expression in OSCC patients were most enriched. In conclusion, SKA1 is a novel oncogene in OSCC that enhances proliferation, migration, and resistance to irradiation in OSCC and premalignant cells.