Abstract C281: The carcinogen cadmium promotes activation of lysine 63 (K63)- linked ubiquitin-dependent signaling by inhibiting selective autophagy and CYLD K63 deubiquitination.

K63-linked ubiquitination– i.e. conjugation of a chain of ubiquitins (Ub) linked through lysine 63– has emerged as a key mechanism regulating signaling transduction pathways. Although critical, very little information is currently available about how subversion of K63 ubiquitination might contribute to inflammatory diseases and cancers. The present study provides the first evidence that cadmium (Cd), a widespread environmental carcinogen, is a powerful activator of K63 ubiquitination. Indeed, Cd induces accumulation of K63 polyubiquitinated proteins, independently of oxidative damage, activation of ubiquitin ligase or proteasome impairment. Rather, we demonstrate that Cd activates K63 ubiquitination by inhibiting both CYLD and autophagy, two tumor suppressors that selectively deubiquitinate and degrade K63-linked ubiquitinated proteins, respectively. As a result, we found that cadmium treatment induces sustained activation of NF-κB, a pathway critically dependent on K63 ubiquitination. Given the role of NF-κB in survival, proliferation, and inflammation, these findings provide a potential molecular link between cadmium exposure and the increased incidences of inflammatory diseases and cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C281. Citation Format: Abderrahman Chargui, Amine Belaid, Veronique Imbert-Rezzonico, Michel Samson, Jean-Marie Guigonis, Sebastien L'hoste, Michel Tauc, Jean Francois Peyron, Philippe Poujeol, Paul Hofman, Baharia Mograbi. The carcinogen cadmium promotes activation of lysine 63 (K63)-linked ubiquitin-dependent signaling by inhibiting selective autophagy and CYLD K63 deubiquitination. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C281.