Sharpin Stabilizes Beta-Catenin Through A Linear Ubiquitination-Independent Manner To Support Gastric Tumorigenesis

Background Aberrant activation of Wnt/beta-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/beta-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity.Methods The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/beta-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of beta-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo.Results Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with beta-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase beta-Trcp1 for beta-catenin binding, thereby decreasing beta-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner beta-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with beta-catenin expression levels.Conclusions Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/beta-catenin signaling via SHARPIN-mediated stabilization of beta-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive beta-catenin signaling in a subset of human gastric cancers.