Introduction:
Experimental and clinical studies support a model in which a distinct subpopulation
of invasive and therapy resistant cancer cells drives treatment failure in head and
neck cancer (HNC). Common features of this subpopulation are a high degree of cellular
plasticity and acquisition of a phenotype, which is known as epithelial-to-mesenchymal
transition. Recently, we unraveled the transcription factor SOX2 as a key regulator
of cancer cell plasticity, but the mode of SOX2 regulation remained largely elusive.
Methods:
Immunofluorescence staining of cancer cells in 2D and 3D models was done to investigate
SOX2 expression on a single cell level. HNC cells were treated with Decitabine (DAC),
a potent DNMT inhibitor, to address the impact of DNA methylation on SOX2 expression
and cancer cell motility. Integrative multi-scale analysis was performed on global
genome, methylome and transcriptome data, which were available for a cohort of 80
HNC patients. Data were confirmed with public available data from the TCGA-HNC cohort.
Results:
Heterogeneous SOX2 expression was detected for several HNC cell lines in 2D and 3D
models, and loss of SOX2 was a characteristic feature for cells with migratory and
invasive properties. DAC treatment restored SOX2 expression accompanied by a decrease
in cancer cell migration and invasion, suggesting regulation of heterogeneous SOX2
expression by DNA methylation. In line with this assumption, SOX2 gene promoter methylation
was found as a common event in a HNC patient cohort and was confirmed in the TCGA-HNC
cohort.
Conclusion:
Epigenetic regulation of SOX2 expression by DNA methylation regulates tumor cell plasticity
and motility, and treatment with DNMT inhibitors serves as a promising new strategy
to prevent tumor cell dissemination.
