Abstract
<title>Abstract</title> <p>Background Aberrant activation of YAP/TAZ, the effectors of the Hippo pathway, is involved in the proliferation and progression of oral squamous cell carcinoma (OSCC). However, many aspects of the tumor-promoting mechanisms associated with YAP/TAZ activation remain unclear. In this study, we aimed to identify the key proliferation-asssociated genes regulated by YAP/TAZ in OSCC. Methods Cell culture, western blot assays, RNA-seq analysis, knockdown experiments, phosphoproteomic analysis, and gene set enrichment analyses were performed to examine and validate the YAP/TAZ-regulated proliferation-associated genes in OSCC. Results RNA-seq analysis indicated alpha-protein kinase 2 (ALPK2) upregulation upon YAP/TAZ activation. YAP/TAZ-related genes were significantly enriched in the ALPK2 high-expression groups of cancer cell lines and tissues. Further, ALPK2 KD significantly inhibited the proliferation of YAP/TAZ-activated OSCC and EGFR-mutant lung adenocarcinoma cells. Phosphoproteomic and RNA-seq analyses revealed altered expression of MTA2-, and AP-1-related molecules, suggesting that these signaling pathways may be involved in the tumor-promoting effects of ALPK2. Conclusions ALPK2 may contribute to cell proliferation in YAP/TAZ-activated cancers and the MTA2 and AP-1-related signaling pathways may be involved in its function. Overall, ALPK2 may serve as a novel therapeutic target in OSCC, and its molecular mechanisms need to be examined further.</p>