title: ΔNp63α activates CD82 metastasis suppressor to inhibit cancer cell invasion.
abstract: P63 is a p53 family member involved in multiple facets of biology, including embryonic development, cell proliferation, differentiation, survival, apoptosis, senescence and aging. The p63 gene encodes multiple protein isoforms either with (TAp63) or without (ΔNp63) the N-terminal transactivation domain. Amounting evidence suggests that p63 can function as a tumor suppressor, yet the precise molecular mechanisms, and particularly the specific roles of TAp63 and ΔNp63 in cancer progression, are still largely unclear. Here, we demonstrated that ΔNp63α, the predominant isoform expressed in epithelial cells and squamous cell carcinomas, inhibits cell invasion. Affymetrix gene expression profiling, combined with gain- and loss-of-function analyses and chromatin immunoprecipitation, indicated that cluster of differentiation 82 (CD82), a documented metastasis suppressor, is a direct transcriptional target of ΔNp63α. Expression of ΔNp63α inhibited outgrowth in Matrigel and cancer cell invasion, which was largely reversed by specific ablation of CD82. Conversely, ΔNp63α knockdown led to increased cell invasion, which was reversed by ectopic expression of CD82. Moreover, inhibition of glycogen synthase kinase-3β (GSK3β) by either pharmacological inhibitors or by RNA interference resulted in the downregulation of ΔNp63α and CD82 expression, concomitant with increased cell invasion, independently of β-catenin. Furthermore, decreased expression of p63 and CD82 is correlated with cancer progression. Taken together, this study reveals that ΔNp63α upregulates CD82 to inhibit cell invasion, and suggests that GSK3β can regulate cell invasion by modulating the ΔNp63α-CD82 axis.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China.
authors.forename: S
authors.initials: S
authors.lastname: Liang
authors.affiliation: Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China.
authors.forename: J
authors.initials: J
authors.lastname: Bergholz
authors.affiliation: Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China.
authors.forename: H
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Walsh
authors.affiliation: Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China.
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Xiao
mesh_terms: D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051861:Kangai-1 Protein / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497688:CD82 protein, human; D051861:Kangai-1 Protein; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3