The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth

• Published in: Oncogene Vol. 35; no. 24; pp. 3114 - 3124
• Main Authors: Palazzo, E, Kellett, M, Cataisson, C, Gormley, A, Bible, P W, Pietroni, V, Radoja, N, Hwang, J, Blumenberg, M, Yuspa, S H, Morasso, M I
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-06-2016; Nature Publishing Group
• Subjects: 631/136/142; 631/67; Animals; Apoptosis; Carcinogenesis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Care and treatment; Cell Biology; Cell cycle; Cell Cycle Checkpoints; Cell differentiation; Cell Differentiation - physiology; Cell migration; Cell Proliferation - physiology; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Development and progression; Disease Progression; Female; Gene expression; Genetic aspects; Genetic transcription; Health aspects; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Homeostasis; Human Genetics; Humans; Hyperplasia; Internal Medicine; Keratinocytes; Male; Medicine; Medicine & Public Health; Mice; Oncology; original-article; p53 Protein; Phenotypes; Properties; Proteins; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Squamous cell carcinoma; Transcription; Transcription factors; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptomics; Transfection; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.380

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.