Parakeratosis in skin is associated with loss of inhibitor of differentiation 4 via promoter methylation

SummaryParakeratosis refers to incomplete maturation of epidermal keratinocytes, resulting in abnormal retention of nuclei in the stratum corneum. It occurs in many diseases of the skin, particularly in psoriasis. Down-regulation of inhibitor of differentiation 4 messenger RNA has been demonstrated in psoriatic skin, but the specificity and mechanism for this finding are unknown. In this study, we addressed specificity by immunohistochemical staining for inhibitor of differentiation 4 protein in skin disorders showing parakeratosis, including: psoriasis (n = 9), chronic eczema (n = 6), and squamous cell carcinoma (n = 7). In these conditions, parakeratotic keratinocytes in the upper layers of the skin lacked inhibitor of differentiation 4 protein expression, whereas keratinocytes in the lower layers were densely stained, in contrast to diffuse expression in normal skin. Because promoter hypermethylation of inhibitor of differentiation 4 has been described in several cancers, we determined the methylation pattern of the inhibitor of differentiation 4 promoter in psoriasis and compared this with squamous cell carcinoma. We found a novel methylation pattern of the inhibitor of differentiation 4 promoter in both conditions. Inhibitor of differentiation 4 promoter methylation was significantly increased in psoriasis (34.8%) and squamous cell carcinoma (21.8%), compared with normal skin (0%). Moreover, cells in the upper and lower parts of psoriatic epidermis were, respectively, hypermethylated and nonmethylated, at the inhibitor of differentiation 4 promoter. Comparable studies in several cell lines confirmed that hypermethylation of the promoter was associated with loss of inhibitor of differentiation 4 messenger RNA and protein expression. Our study demonstrates a previously unreported link between gene-specific promoter hypermethylation and abnormal cellular differentiation in several skin diseases. This mechanism might provide clues for novel therapies for skin disorders characterized by parakeratosis.