title: ΔNp63α induces the expression of FAT2 and Slug to promote tumor invasion.
abstract: Tumor invasion can be induced by changes in gene expression that alter cell phenotype. The transcription factor ΔNp63α promotes basal-like breast cancer (BLBC) migration by inducing the expression of the mesenchymal genes Slug and Axl, which confers cells with a hybrid epithelial/mesenchymal state. However, the extent of the ΔNp63α regulated genes that support invasive behavior is not known. Here, using gene expression analysis, ChIP-seq, and functional testing, we find that ΔNp63α promotes BLBC motility by inducing the expression of the atypical cadherin FAT2, the vesicular binding protein SNCA, the carbonic anhydrase CA12, the lipid binding protein CPNE8 and the kinase NEK1, along with Slug and Axl. Notably, lung squamous cell carcinoma migration also required ΔNp63α dependent FAT2 and Slug expression, demonstrating that ΔNp63α promotes migration in multiple tumor types by inducing mesenchymal and non-mesenchymal genes. ΔNp63α activation of FAT2 and Slug influenced E-cadherin localization to cell-cell contacts, which can restrict spontaneous cell movement. Moreover, live-imaging of spheroids in organotypic culture demonstrated that ΔNp63α, FAT2 and Slug were essential for the extension of cellular protrusions that initiate collective invasion. Importantly, ΔNp63α is co-expressed with FAT2 and Slug in patient tumors and the elevated expression of ΔNp63α, FAT2 and Slug correlated with poor patient outcome. Together, these results reveal how ΔNp63α promotes cell migration by directly inducing the expression of a cohort of genes with distinct cellular functions and suggest that FAT2 is a new regulator of collective invasion that may influence patient outcome.
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX 75390-8807, USA.
authors.forename: Tuyen T
authors.initials: TT
authors.lastname: Dang
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX 75390-8807, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Westcott
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX 75390-8807, USA.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Maine
authors.affiliation: McDermott Center for Human Growth and Disease, University of Texas, Southwestern Medical Center, Dallas, TX 75390-8807, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kanchwala
authors.affiliation: McDermott Center for Human Growth and Disease, University of Texas, Southwestern Medical Center, Dallas, TX 75390-8807, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX 75390-8807, USA.|Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX 75390-8807, USA.
authors.forename: Gray W
authors.initials: GW
authors.lastname: Pearson
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D015820:Cadherins; C502404:FAT2 protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
keywords: FAT2; Slug; breast cancer; invasion; p63