Reversible SUMOylation of TBL1-TBLR1 regulates β-catenin-mediated Wnt signaling.

Dysregulation of Wnt signaling has been implicated in tumorigenesis. The role of Transducin β-like proteins TBL1-TBLR1 in the promotion of Wnt/β-catenin-mediated oncogenesis has recently been emphasized; however, the molecular basis of activation of Wnt signaling by the corepressor TBL1-TBLR1 is incompletely understood. Here, we show that both TBL1 and TBLR1 are SUMOylated in a Wnt signaling-dependent manner, and that this modification is selectively reversed by SUMO-specific protease I (SENP1). SUMOylation dismissed TBL1-TBLR1 from the nuclear hormone receptor corepressor (NCoR) complex, increased recruitment of the TBL1-TBLR1-β-catenin complex to the promoter of Wnt target genes, and consequently led to activation of Wnt signaling. Conversely, SENP1 decreased formation of the TBL1-TBLR1-β-catenin complex, leading to inhibition of β-catenin-mediated transcription. Importantly, inhibition of SUMOylation significantly decreased the tumorigenicity of SW480 colon cancer cells. Thus, our data reveal a mechanism for activation of Wnt signaling via the SUMOylation-dependent disassembly of the corepressor complex.