Over-activation of SUMOylation is correlated with poor prognosis in multiple myeloma (MM), with the mechanism unclear. Wnt signaling is one of the aberrantly regulated pathways related to cancer tumorigenesis and progression. Whether SUMOylation is involved in regulating the activity of Wnt/β-catenin pathway, however, has not been reported in MM. Here we found that the TOPflash reporter activity and the expression of Wnt/β-catenin target genes can be down-regulated after interference with SUMOylation through SUMO-1 small interfering RNA (siRNA). SUMOylation inhibition down-regulated β-catenin at protein level via promotion of ubiquitin-proteasomal mediated degradation. Furthermore, over-expression of β-catenin rescued Wnt/β-catenin pathway activity and partially prevented increased apoptosis and growth inhibition induced by SUMOylation inhibition, indicating that β-catenin was responsible for the observed effect on Wnt/β-catenin pathway. To gain a clearer view, we exploited the inter-protein interactions of β-catenin and SUMO-1 in myeloma cell lines. Immunoprecipitation and immunofluorescence assay proved that β-catenin is subjected to SUMOylation in vivo, which may, at least partially explain the impact of SUMOylation inhibition on β-catenin. The association of SUMO-1 and β-catenin was confirmed in myeloma patient samples. Taken together, our data proved that SUMOylation inhibition down-regulates Wnt/β-catenin pathway by promoting the ubiquitin-proteasomal mediated degradation of β-catenin. SUMOylation of β-catenin is part of the mechanisms involved in the dysregulated proliferation of myeloma cells.
Keywords: Multiple myeloma; SUMO-1; SUMOylation; Wnt/β-catenin.