title: ΔNp63 versatilely regulates a Broad NF-κB gene program and promotes squamous epithelial proliferation, migration, and inflammation.
abstract: Head and neck squamous cell carcinoma (HNSCC) and many other epithelial malignancies exhibit increased proliferation, invasion, and inflammation, concomitant with aberrant nuclear activation of TP53 and NF-κB family members ΔNp63, cRel, and RelA. However, the mechanisms of cross-talk by which these transcription factors coordinate gene expression and the malignant phenotype remain elusive. In this study, we showed that ΔNp63 regulates a cohort of genes involved in cell growth, survival, adhesion, and inflammation, which substantially overlaps with the NF-κB transcriptome. ΔNp63 with cRel and/or RelA are recruited to form novel binding complexes on p63 or NF-κB/Rel sites of multitarget gene promoters. Overexpressed ΔNp63- or TNF-α-induced NF-κB and inflammatory cytokine interleukin-8 (IL-8) reporter activation depended on RelA/cRel regulatory binding sites. Depletion of RelA or ΔNp63 by small interfering RNA (siRNA) significantly inhibited NF-κB-specific, or TNF-α-induced IL-8 reporter activation. ΔNp63 siRNA significantly inhibited proliferation, survival, and migration by HNSCC cells in vitro. Consistent with these data, an increase in nuclear ΔNp63, accompanied by increased proliferation (Ki-67) and adhesion (β4 integrin) markers, and induced inflammatory cell infiltration was observed throughout HNSCC specimens, when compared with the basilar pattern of protein expression and minimal inflammation seen in nonmalignant mucosa. Furthermore, overexpression of ΔNp63α in squamous epithelial cells in transgenic mice leads to increased suprabasilar cRel, Ki-67, and cytokine expression, together with epidermal hyperplasia and diffuse inflammation, similar to HNSCC. Our study reveals ΔNp63 as a master transcription factor that, in coordination with NF-κB/Rels, orchestrates a broad gene program promoting epidermal hyperplasia, inflammation, and the malignant phenotype of HNSCC.
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Xinping
authors.initials: X
authors.lastname: Yang
authors.forename: Hai
authors.initials: H
authors.lastname: Lu
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.forename: Rose-Anne
authors.initials: RA
authors.lastname: Romano
authors.forename: Yansong
authors.initials: Y
authors.lastname: Bian
authors.forename: Jay
authors.initials: J
authors.lastname: Friedman
authors.forename: Praveen
authors.initials: P
authors.lastname: Duggal
authors.forename: Clint
authors.initials: C
authors.lastname: Allen
authors.forename: Ryan
authors.initials: R
authors.lastname: Chuang
authors.forename: Reza
authors.initials: R
authors.lastname: Ehsanian
authors.forename: Han
authors.initials: H
authors.lastname: Si
authors.forename: Satrajit
authors.initials: S
authors.lastname: Sinha
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics*; D010641:Phenotype; D010750:Phosphoproteins / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D016209:Interleukin-8; D019394:Ki-67 Antigen; D016328:NF-kappa B; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins