Histone methylation defines c-Jun/Sox2/Hif1a axis that controls cancer stemness and tumor progression in squamous cell carcinoma

Squamous cell carcinomas (SCCs) originate from various anatomical sites that show poor prognosis and survival due to the presence of cancer stem cells (CSCs) that impart resistance to therapy. However, the synergistic role of epigenetic modifications, cell signaling, and metabolic regulation involved in cancer stemness, tumorigenic potential, and metastasis is poorly understood in both skin and oral SCC. In this study, the whole transcriptomic profile of sorted CSCs from advanced-stage skin SCC patients shows an upregulation of epigenetic modifiers (EZH2, DNMT3A, DNMT3B), which increases global DNA hypermethylation, further leading to upregulation of non-canonical Wnt signaling (WNT7B, c-JUN) and metabolic reprogramming through hypoxia-inducible factor (HIF1a) and glycolysis (SLC2A2, HK2, LDHA). Importantly, the combination of Decitabine (DAC), a DNA methyltransferase inhibitor, and RAC1 non- canonical Wnt signaling inhibitor in both skin and oral SCC xenograft mice models reveals a reduction in the global DNA hypermethylation, non-canonical Wnt signaling, leading to decrease glycolysis, cancer stemness, and tumorigenic potential in both skin and oral SCC. Overall, our study uncovers crosstalk among epigenetic, non-canonical Wnt signaling and metabolism (c- Jun/Sox2/Hifa) in both skin and oral SCC. Thus, the combination of DAC and RAC1 inhibitor holds promise to improve clinical outcomes in skin and oral SCC patients.