Table 2.

DNA methylation changes associated with cSCC.

Epigenetic Changes	Involved Gene	Involved Protein	Role of the Protein	Results
DNA methylation of CpG, leading to loss of function	CDH1 gene promoter (E-cadherin gene promoter)	E-cadherin	Intercellular adhesion molecule	Hypermethylation of this gene is more frequent in invasive forms of SCC compared to AK and normal population. Hypermethylation of CDH1 gene promoter is present in 95% of cutaneous squamous cell carcinoma samples [63,64].
DNA methylation of CpG, leading to loss of function	CDH13 gene promoter (T-cadherin gene promoter)	T-cadherin	Cell migration; Phenotypic changes; Calcium ion transport	Hypermethylation of T-cadherin gene promoter is associated with phenotypic cellular changes, both in SCC and in actinic keratoses that will evolve into invasive SCC [65,66].
DNA methylation of CpG, leading to loss of function	CDKN2A gene	p16 (ARF)	Tumor suppressor genes—cell cycle regulator proteins	Hypermethylation is associated with a statistically significant decrease in the synthesis of aforementioned proteins (identified by immunohistochemical studies) (p < 0.001), with the inactivation of p16 and p14 [64].
DNA methylation of CpG, leading to loss of function	CDKN2A gene	p14 (INK4A)
DNA methylation of CpG, leading to loss of function	Retinoblastoma protein 1 (RB1) gene	RB1
DNA methylation of CpG, leading to loss of function	SFRP1-5 promoter gene	SFRP1-5 glycoproteins	Modulatory effects on Wnt pathway	Hypermethylation of the promoter region of these genes leads to a decrease in the expression of SFRP1-5 proteins in cSCC. It can be used as a marker of cSCC [67].
DNA methylation of CpG, leading to loss of function	FRZB (frizzled-related protein) promoter gene	FRZB protein	Modulatory effects on Wnt pathway—involved in cell growth and differentiation	Hypermethylation of the promoter of this gene is significantly higher in metastatic cSCC compared to non-metastatic forms (p = 0.00004). It can be used as a marker of subtypes with aggressive evolution [68].
DNA methylation of CpG, leading to loss of function	Death-associated protein kinase 1 (DAPK1) gene	DAPK1	Tumor suppressor activity—protein involved in apoptosis and autophagy	DAPK1 hypermethylation is much more frequent in invasive forms of cSCC [66].