KIT promoter: Structure, function and targeting

In the last two decades, the design of new drugs able to selectively recognize noncanonical structures at the promoter of oncogenes has received much attention as potential anticancer agents with limited side effects. In order to result in an effective treatment some conditions must be fulfilled: – there must be a strong correlation between oncoprotein expression and the induction/sustainment of the cancer, – the noncanonical DNA structure must be directly involved in the control of the correct recruitment of the transcriptional machinery, – the target site must be as much as possible unique inside the cell. In this scenario, the proximal promoter of the proto-oncogene KIT represents a fascinating model. Indeed, hyper-activation/expression of the c-kit oncoprotein is directly related to the development of several cancers and a complex network of transcription factors bind the promoter to regulate its production. Moreover, their binding sites cover a domain where up to three G-quadruplexes can form. Here, we present an updated overview of the currently available data on the biological relevance of this proto-oncogene and on the functions controlled at the level of its promoter. The possibilities to therapeutically exploit this features will be subsequently discussed in the light of a number of structural studies covering the polymorphic behavior of the guanine-rich clusters located in the proximal domain upstream of the transcription starting site.