Nuclear versus cytoplasmic IKKα signaling in keratinocytes leads to opposite skin phenotypes and inflammatory responses, and a different predisposition to cancer

Author Contribution: VAGG and JPA conducted most of the experiments with assistance from AP, RMG, MN, AR and MLC. VAGG, AP, JMP, RAGF, MJFA, MN, AB and MLC analyzed data. MN, VAGG and MLC designed research studies. RGE, MN, JMP and MLC performed genomic analysis. Writing the manuscript: MLC. AB, RAGF and MJFA wrote histological results. Revising the manuscript: MN, RGE, JMP, AR, RAGF, AB, MLC. The order of the co–first authors was assigned based on their efforts and contributions to the study RMG is a recipient of an ISCII/HFIBH12O contract ; IKKα is known as an essential protein for skin homeostasis. However, the lack of suitable models to investigate its functions in the skin has led to IKKα being mistakenly considered as a suppressor of non-melanoma skin cancer (NMSC) development. In this study, using our previously generated transgenic mouse models expressing exogenous IKKα in the cytoplasm (C-IKKα mice) or in the nucleus (N-IKKα mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKα differently regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, and for the cutaneous inflammatory response. In addition, each type of IKKα-transgenic mice shows different predisposition to the development of spontaneous NMSC. Specifically, N-IKKα mice display an atrophic epidermis with exacerbated terminal differentiation, signs of premature skin aging, premalignant lesions, and develop squamous cell carcinomas (SCCs). Conversely, C-IKKα mice, whose keratinocytes are nearly devoid of endogenous nuclear IKKα, do not develop skin SCCs, although they exhibit hyperplastic skin with deficiencies in terminal epidermal differentiation, chronic cutaneous inflammation, and constitutive activation of STAT-3 and NF-κB signaling pathways. Altogether, our data demonstrate that alterations in the localization of IKKα in the nucleus or cytoplasm of keratinocytes cause opposite skin changes and differentially predispose to the growth of ...