ΔNp63 versatilely regulates a broad NF-κB gene program and promotes squamous epithelial proliferation, migration, and inflammation

Xinping Yang, Hai Lu, Bin Yan, Rose Anne Romano, Yansong Bian, Jay Friedman, Praveen Duggal, Clint Allen, Ryan Chuang, Reza Ehsanian, Han Si, Satrajit Sinha, Carter Van Waes, Zhong Chen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3688-3700
Number of pages13
JournalCancer Research
Volume71
Issue number10
DOIs
StatePublished - May 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Yang, X., Lu, H., Yan, B., Romano, R. A., Bian, Y., Friedman, J., Duggal, P., Allen, C., Chuang, R., Ehsanian, R., Si, H., Sinha, S., Van Waes, C., & Chen, Z. (2011). ΔNp63 versatilely regulates a broad NF-κB gene program and promotes squamous epithelial proliferation, migration, and inflammation. Cancer Research, 71(10), 3688-3700. https://doi.org/10.1158/0008-5472.CAN-10-3445