Histone methylation defines c-Jun/Sox2/Hif1α axis that controls stemness and tumor progression in squamous cell carcinoma

Squamous cell carcinomas (SCCs) originate from various sites that show poor survival due to the presence of cancer stem cells (CSCs), which impart therapy resistance. However, the crosstalk of molecular mechanisms regulating CSCs maintenance in skin and oral SCC is poorly understood. Here, we show that the whole-transcriptome profile of CSCs from skin SCC patients reveals upregulation in expression of genes associated with global hypermethylation, enhanced non-canonical Wnt signaling, and glycolysis, thereby activating the c-Jun/Sox2/Hif1α axis. Thus, it suggests crosstalk among epigenetics/signaling/metabolism in skin and oral SCC. Importantly, the combination of Decitabine (DAC), a methyltransferase inhibitor, and a RAC1 non-canonical Wnt inhibitor (RAC1i) in skin and oral SCC xenograft mouse models reduces global hypermethylation and non-canonical Wnt signaling, thereby attenuating the c-Jun/Sox2/Hif1α axis, stemness, and tumorigenic potential. Overall, our findings show that the combination of DAC and RAC1i may improve the clinical outcomes in patients with skin and oral SCC. Squamous cell carcinomas (SCCs) show poor survival due to the presence of cancer stem cells (CSCs). Here, the authors delineate the molecular mechanism underlying SCC progression by identifying a crosstalk of epigenetic-signaling metabolism axis, which showed global hypermethylation activates non-canonical Wnt signaling, in turn activating glycolysis in skin and oral SCC.