The role of Twist1 in UVB-induced skin carcinogenesis

The transcription factor Twist1 has been reported to be essential for the formation and invasiveness of chemically induced tumors in mouse skin. However, the impact of keratinocyte specific Twist1 deletion on carcinogenesis caused by UVB radiation has not been clarified. In the current studies, we demonstrate that deletion of Twist1 in skin keratinocytes in vivo (using K5-Cre x Twist1[superscript flox/flox] mice; Twist1 KO mice) significantly suppressed UVB-induced skin carcinogenesis. Twist1 KO led to reduced UVB-induced epidermal hyperproliferation. Proliferation analysis by Ki67 immunofluorescence staining as well as BrdU incorporation showed a significant decrease in Twist1 KO epidermis. In addition, Twist1 was also found to control the differentiation of keratinocytes in the bulge region and in the interfollicular epidermis, suggesting that exit from cell cycle in Twist1 KO keratinocytes is linked to induction of differentiation. Deletion of Twist1 in vivo and in culture showed significant induction of early and late differentiation markers including TG1, K1, OVOL1, Loricrin and Filaggrin. In contrast, overexpression of Twist1 in cultured keratinocytes suppressed expression of calcium-induced differentiation markers. Additionally, deletion of Twist1 in epidermal and bulge region keratinocytes led to depletion of several hair follicle stem/progenitor markers, including CD34, Lrig1, Lgr5 and Lgr6. These findings further support the hypothesis that Twist1 may have direct role in regulating proliferation, differentiation and self-renewal processes in the epidermis. We also discovered that the natural compound, Harmine, leads to degradation of Twist1 in keratinocytes and inhibits UVB-induced epidermal proliferation while stimulating keratinocyte differentiation similar to Twist1 KO. Collectively, the current data demonstrate an important role for Twist1 in UVB skin carcinogenesis and the potential for this transcription factor as a target for skin cancer prevention