title: The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth.
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.
authors.affiliation: Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Palazzo
authors.affiliation: Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kellett
authors.affiliation: Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cataisson
authors.affiliation: Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gormley
authors.affiliation: Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Bible
authors.affiliation: Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA.
authors.forename: V
authors.initials: V
authors.lastname: Pietroni
authors.affiliation: Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA.
authors.forename: N
authors.initials: N
authors.lastname: Radoja
authors.affiliation: Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Dermatology, New York University, New York, NY, USA.
authors.forename: M
authors.identifier: 0000-0002-8672-7774
authors.initials: M
authors.lastname: Blumenberg
authors.affiliation: Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, MD, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Yuspa
authors.affiliation: Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Morasso
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53