TNF-α Promotes c-REL/ΔNp63α Interaction and TAp73 Dissociation from Key Genes That Mediate Growth Arrest and Apoptosis in Head and Neck Cancer

Abstract

Inflammation-induced activation of proto-oncogenic NF-κB/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 co-expressed and complex with ΔNp63α in the nucleus of a subset of head and neck squamous cell carcinoma (HNSCC) cell lines with mutant (mt)TP53. TNF-α a pro-inflammatory cytokine, promoted nuclear translocation and c-REL/ΔNp63α interaction and dissociation of TAp73 from nuclear ΔNp63α to the cytoplasm, while c-REL siRNA depletion attenuated this effect. Overexpression of c-REL or a c-REL κB-site DNA binding mutant enhanced protein interaction withΔNp63α and TAp73 dissociation, implicating c-REL/ΔNp63α-specific interactions in these effects. We discovered TNF-α- or genetic alteration of c-REL expression inversely modulatesΔNp63α/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 anti-proliferative effects of TNF-α or TAp73. Conversely, c-REL siRNA depletion enhanced TAp73 promoter interaction, and expression of genes mediating growth arrest and apoptosis. Similar to TNF-α treated HNSCC lines, human HNSCC tumors and hyperplastic squamous epithelia of transgenic mice overexpressing ΔNp63α that exhibit inflammation, also demonstrate increased nuclear c-REL/ΔNp63α and cytoplasmic TAp73 localization. These findings unveil a novel and reversible dynamic mechanism whereby pro-inflammatory cytokine TNF-α-induced c-REL/ΔNp63α interactions inactivate tumor suppressor TAp73 function, promoting TNF-α resistance and cell survival in cancers with mtTP53.

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

“…Second, the copy number data when aligned with TP53 missense and truncating mutations, reveals more loss of heterozygosity (LOH) in the C9-OV and C4-BRCA/Basal than in the C2-Squamous-like samples. The apparent higher TP53-pathway activity in C2-Squamous-like tumors may be related to the expression of isoforms of related family members TP63 and/or TP73 (Figure 5B), which may compensate for TP53 mutation in the C2-Squamous-like tumors as revealed by PARADIGM-Shift analysis (Figure 5C), and as supported by functional experimental data in HNSC lines and tumors (Lu et al, 2011). In HNSC, the function of TP63/73 in growth of HNSC is modulated in the presence of inflammatory factor TNF-α and cREL.…”

Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy

“…Also, the anti-IL-6 receptor antibody tocilizumab21 has shown efficacy in both inducing and maintaining remission in CD; whether IL-6 blockade might confer additional benefits to anti-TNFα non-responders, however, has not yet been examined. It is not surprising that many of the genes regulated by anti-TNFα antibodies, both in responders and non-responders, are known to be dependent upon TNFα signalling (ie, the apoptosis-inducing p53 target PMAIP1),22 the TNFα-induced proteins TNFAIP3 and TNFAIP8, and the NF-κB-dependent TNFα-induced genes CD69,23 24 MMP9,25 VCAM1,26 PLAU (urokinase-type plasminogen activator)27 and CD83 28. The regulation of this gene set by anti-TNFα antibodies, even in non-responders, suggests that the lack of response to anti-TNFα in these patients may not reflect the absence of biological activity of the administered antibody.…”

ΔNp63α represses anti-proliferative genes via H2A.Z deposition

“…gov/tcga) indicates that 196 of the 215 genes up-regulated upon DNp63a knockdown in H226 cells have a reduced expression in numerous lung SCC cells as compared with normal tissue (Supplemental Tables 1, 2). Studies of SCC cells expressing endogenous DNp63a differ in the degree to which canonical p53 target genes, including p21, MDM2, BAX, NOXA, or PUMA, are repressed by DNp63a (Barbieri et al 2005;Rocco et al 2006;Gu et al 2008;Lu et al 2011). Here our efforts revealed a group of anti-proliferative genes repressed by DNp63a across SCC cell types of diverse origin regardless of p53 status, including IGFBP3 and SAMD9L, whose knockdown rescues the proliferation arrest caused by DNp63a depletion in H226 cells.…”