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

  • Nat Commun. 2026 Apr 27;17(1):5753. doi: 10.1038/s41467-026-71996-7.
Darshan Mehta  1  2 ,  Akshay Paradkar  1  2 ,  Bharat Rekhi  3 ,  Prakash Nayak  4 ,  Bhabani Mohanty  5 ,  Pradip Chaudhari  2  5 ,  Poonam Gera  6 ,  Swapnil Rane  2  7 ,  Pankaj Chaturvedi  8 ,  Sanjeev K Waghmare  9  10
Affiliations
  • 1. Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.
  • 2. Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
  • 3. Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
  • 4. Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
  • 5. Small Animal Imaging Facility (SAIF), Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.
  • 6. Cancer Research Institute, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.
  • 7. Department of Pathology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.
  • 8. Tata Memorial Centre-Advanced Centre for Treatment Research and Education in Cancer ACTREC, Kharghar, Navi Mumbai, Maharashtra, India.
  • 9. Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India. [email protected].
  • 10. Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India. [email protected].
PMID: 42045185 DOI: 10.1038/s41467-026-71996-7
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.

Products