Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking

Nuclear factor-kappa B (NF-kappa B) and insulin-like growth factor-1 (IGF-1)-mediated signaling is associated with different tumors including renal cell carcinoma. NF-kappa B- and IGF-1-mediated signaling is found to be inhibited in the presence of wild-type von Hippel-Lindau (VHL) tumor suppresser gene. Therefore, negative regulator of VHL may be a good target for regulating NF-kappa B and IGF-1R. In this study, we found that VHL, a tumor suppressor protein that downregulates the NF-kappa B activity and the stability of IGF-1R was depleted by TGase 2 through polymerization via crosslinking and proteasomal degradation in kidney, breast and ovary cancer cell lines. We also found that TGase 2 knockdown promotes hypoxia-inducible factor 1 alpha (HIF-1 alpha) degradation, and thereby decrease HIF-1 alpha transcriptional activity. Importantly, VHL expression was decreased in vivo in TGase-2-transgenic mice, and this was associated with increased NF-kappa B activity and the levels of expression of IGF-1R, HIF-1 alpha and erythropoietin in kidney tissue. These results suggest a novel mechanism of regulation of the VHL tumor suppressor by TGase 2 that appears to be independent of the known cancer regulatory mechanisms. Oncogene (2011) 30, 4780-4790; doi: 10.1038/onc.2011.183; published online 30 May 2011