Abstract 3900: Nuclear c-REL displaces p73 in partnering with DNp63 to suppress p21 expression and promote proliferation in head and neck cancer

Abstract

Abstract The tumor suppressor p53 is known as the ‘guardian of the genome’ owing to its ability to integrate many signals that control cell life or death. But the functions of the p53 tumor suppressor are commonly lost in cancer. The p53 family members p63 and p73 also contribute to tumor-suppressor function, because they share many common transcriptional targets with p53 and their activities contribute to the p53-dependent apoptosis and cell cycling of cancer cells. In p53 mutant tumors, TAp73 or TAp63 isoforms may compensate for p53 loss and respond to cell stress by upregulating genes involved in growth arrest and apoptosis. In contrast, DNp63 and DNp73 counteract the activities of TA isoforms, either by competing for common DNA binding elements or by blocking the TAp63 and TAp73 isoforms through direct protein-protein interactions. The mechanism regulating TA and DN crosstalk and balance remains uncertain. We recently reported that p53 and NF-KappaB family members DNp63 and c-Rel can interact to repress p21Cip1 and growth arrest in normal murine keratinocytes. Here we show that c-Rel, p63, and p73 exhibit aberrant expression and nuclear localization in a subset of head and neck squamous cell carcinoma (HNSCC). Co-immunoprecipitation, electromobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP) studies revealed that TNFalpha-induced or overexpressed nuclear c-Rel interact with DNp63, displace TAp73 from the nucleus, and from p63 promoter regulatory motifs of cell cycle and apoptotic genes p21, NOXA and PUMA. TNFalpha-induced or overexpressed c-Rel repressed, while c-Rel siRNA knockdown enhanced their expression and inhibited cell proliferation and survival. We conclude that aberrant and TNFalpha-mediated activation and interaction of c-Rel/DNp63 can displace TAp73 and block its key function in growth arrest and apoptosis. Our findings support a novel mechanism whereby an inflammatory cytokine, such as TNF-alpha, can promote c-Rel nuclear translocation, interaction with DNp63, and displacement of TAp73, to inhibit expression of key cell cycle inhibitor and apoptotic genes, which are downregulated in HNSCC and other cancers. This represents a novel form of cross-talk between NF-kappaB and TP53 family members and pathways that govern the switch between survival and death signals in HNSCC and other malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3900.