TNF-alpha promotes c-REL/DeltaNp63alpha interaction and TAp73 dissociation from key genes that mediate growth arrest and apoptosis in head and neck cancer.

摘要

Inflammation-induced activation of proto-oncogenic NF-kappaB/REL and dysfunction of tumor suppressor TP53/p63/p73 family transcription factors are key events in cancer progression. How inflammatory signaling coordinates dysregulation of these two transcription factor families during oncogenesis remains incompletely understood. Here, we observed that oncoprotein c-REL and tumor suppressor TAp73 are coexpressed and complex with DeltaNp63alpha in the nucleus of a subset of head and neck squamous cell carcinoma (HNSCC) cell lines with mutant (mt)TP53. TNF-alpha, a proinflammatory cytokine, promoted c-REL nuclear translocation, c-REL/DeltaNp63alpha interaction, and dissociation of TAp73 from DeltaNp63alpha and the nucleus to the cytoplasm, whereas c-REL siRNA knockdown attenuated this effect. Overexpression of c-REL or a c-REL kappaB-site DNA-binding mutant enhanced protein interaction with DeltaNp63alpha and TAp73 dissociation, implicating c-REL/DeltaNp63alpha-specific interactions in these effects. We discovered that TNF-alpha or genetic alteration of c-REL expression inversely modulates DeltaNp63alpha/TAp73 interactions on distinct p63 DNA-binding sites, including those for key growth arrest and apoptotic genes p21WAF1, NOXA, and PUMA. Functionally, c-REL repressed these genes and the antiproliferative effects of TNF-alpha or TAp73. Conversely, c-REL siRNA depletion enhanced TAp73 promoter interaction and expression of genes mediating growth arrest and apoptosis. Similar to TNF-alpha-treated HNSCC lines, human HNSCC tumors and hyperplastic squamous epithelia of transgenic mice overexpressing DeltaNp63alpha that exhibit inflammation also show increased nuclear c-REL/DeltaNp63alpha and cytoplasmic TAp73 localization. These findings unveil a novel and reversible dynamic mechanism whereby proinflammatory cytokine TNF-alpha-induced c-REL/DeltaNp63alpha interactions inactivate tumor suppressor TAp73 function, promoting TNF-alpha resistance and cell survival in cancers with mtTP53.