Waterpipe smoke condensate activates the oncogenes and promotes epithelial–mesenchymal transition to cause oral cancer

Oral squamous cell carcinoma (OSCC) is a significant health challenge, particularly in the Indian subcontinent, where it is the second leading cause of cancer. Smoking, including waterpipe tobacco smoking, is a major risk factor for OSCC and contributes to the onset of malignancy through the absorption of carcinogenic compounds present in tobacco smoke. This study investigated the role of the oncogene Yes-associated protein 1 (YAP1) signaling pathway in OSCC progression, focusing on how exposure to waterpipe smoke condensate (WPSC) influences cellular proliferation, epithelial–mesenchymal transition (EMT), and YAP1 activity. Using immortalized human oral keratinocytes (HOK) and OSCC cell lines, we found that WPSC significantly enhanced cell proliferation, increased colony formation, and elevated YAP1 expression compared to controls. Notably, WPSC treatment resulted in the downregulation of the epithelial marker E-cadherin and the upregulation of mesenchymal markers, indicating a shift towards an invasive phenotype. Further bioinformatic analysis of The Cancer Genome Atlas (TCGA) dataset confirmed that YAP1 is frequently altered in HNSCC, highlighting its role in OSCC carcinogenesis. Our findings establish YAP1 as a central mediator in the response of oral keratinocytes to the oncogenic effects of waterpipe smoking, promoting EMT and enhancing invasive characteristics of OSCC cells. These results underscore the therapeutic potential of targeting the YAP1 signaling pathway in OSCC treatment, particularly in individuals exposed to waterpipe smoke. Future research should elucidate the molecular mechanisms of WPSC-induced YAP1 activation and EMT, paving the way for innovative therapeutic strategies to combat OSCC.