IKKβ (encoded by
IKBKB) is a
protein kinase that regulates the activity of numerous
proteins important in several signaling pathways, such as the NF-κB pathway. IKKβ exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and
oral cancer. In addition, genomic and proteomic studies of human
tumors also indicate that
IKBKB gene is amplified or overexpressed in multiple
tumor types. Here, the relevance of IKKβ in
skin cancer was determined by performing
carcinogenesis studies in animal models overexpressing IKKβ in the basal skin layer. IKKβ overexpression resulted in a striking resistance to
skin cancer development and an increased expression of several
tumor suppressor proteins, such as p53, p16, and p19. Mechanistically, this skin
tumor-protective role of IKKβ is independent of p53, but dependent on the activity of the Ink4a/Arf locus. Interestingly, in the absence of p16 and p19, IKKβ-increased expression favors the appearance of cutaneous spindle cell-like
squamous cell carcinomas, which are highly aggressive
tumors. These results reveal that IKKβ activity prevents skin
tumor development, and shed light on the complex nature of IKKβ effects on
cancer progression, as IKKβ can both promote and prevent
carcinogenesis depending on the cell type or molecular context.Implications: The ability of IKKβ to promote or prevent
carcinogenesis suggests the need for further evaluation when targeting this
protein. Mol
Cancer Res; 15(9); 1255-64. ©2017 AACR.