Abstract
Epidermal homeostasis depends on the coordinated control of keratinocyte cell cycle. Differentiation and the alteration of this balance can result in neoplastic development. Here we report on a novel DLX3-dependent network that constrains epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression. Elevating DLX3 in keratinocytes produces a G1-S blockade associated with p53 signature transcriptional profiles. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinguished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Reinstatement of DLX3 function is sufficient to attenuate the migration of SCC cells, leading to decreased wound closure. Our data establish the DLX3–p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis.
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Acknowledgements
We thank current and past members of the Laboratory of Skin Biology and members of the Laboratory of Cancer Biology and Genetics, and Dr Mark Udey for helpful discussions. We also thank Andrew Ryscavage (LCBG), Gustavo Gutierrez-Cruz (NIAMS Genome Analysis Core Facility), Dr Hong-Wei Sun (Biodata Mining and Discovery Section, NIAMS) and Kristina Zaal of the NIAMS Light Imaging Core Facility. This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (M.I.M. ZIA AR041124-14).
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Palazzo, E., Kellett, M., Cataisson, C. et al. The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth. Oncogene 35, 3114–3124 (2016). https://doi.org/10.1038/onc.2015.380
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DOI: https://doi.org/10.1038/onc.2015.380
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