Abstract
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.
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Acknowledgements
This work was supported by the Advanced Center for Treatment Research and Education in Cancer, Department of Atomic Energy, ACTREC annual fund (grant no. DAE-ACTREC 4598, 4479 to S.K.W). We thank the Tata Memorial Center Research Administration Council for providing financial support (TRAC-3542, IEC#188 to S.K.W). D.M. and A.P. are supported by the ACTREC fellowship. We thank Dr. Akihiko Shimono, Japan, for providing the Sfrp1 knockout mice. We thank Dr. Colin Jamora, Shiv Nadar University, Delhi, for providing the A3886 human skin SCC cell line. We thank Dr. Neelam Shirshat, ACTREC-TMC, Navi Mumbai, for providing Tet-pLKO-puro and TOP/FOP FLSH plasmids. We thank the ACTREC Animal House, small animal imaging facility, flow cytometry, genomic facility, digital imaging, and electron microscopy facilities. We thank the Tumor Tissue Repository, Tata Memorial Hospital, Tata Memorial Center-ACTREC Biorepository, and Department of Pathology for providing tumor tissues. We thank Dr. Sanjay Gupta (Epigenetics and Chromatin Biology Group, ACTREC-TMC, Navi Mumbai) for his valuable insights and suggestions on Decitabine drug and ChIP-qPCR of histone methylation and EMT markers. We thank Dr. Avik Chakraborty (Radiation Medicine Center, BARC, TMH, Mumbai) for allowing us to use the Seahorse xFE24 instrument for understanding glycolysis rate. We thank Mr. Jitendra Gawde (Department of Statistics, ACTREC-TMC, Navi Mumbai) for providing the OS analysis of skin and oral SCC patients and quantitative comparison of IHC H-scores and gene signatures in skin and oral SCC patients. The graphical abstract was prepared using Biorender (Created with https://www.biorender.com/). We have also provided the licensed copy of Biorender (https://biorender.com/j34ubni).
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Mehta, D., Paradkar, A., Rekhi, B. et al. Histone methylation defines c-Jun/Sox2/Hif1α axis that controls stemness and tumor progression in squamous cell carcinoma. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71996-7
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DOI: https://doi.org/10.1038/s41467-026-71996-7
