Title
SUMOylated TβL1/TβLR1 interacts with β-catenin in palmar fascia fibrosis: a novel therapeutic target
Document Type
Article
Publication Date
2019
Abstract
Dupuytren’s Disease (DD) is a benign fibrosis of the palmar fascia, the connective tissue beneath the skin of palm and digits. DD leads to loss of hand function and affects 4 - 6% of the US population alone. Current treatments focus on removing diseased tissue through surgery —however, post-surgery disease recurrence rates exceed 30% with no known cure. Previous studies found that fibroproliferative diseases such as DD contain fibroblasts with abnormally high levels of β-catenin, similar to certain malignancies such as colon cancer. In colon cancer cells, nuclear translocation of β-catenin trans-activates genes responsible for cellular proliferation, and this process is facilitated by the transducin β¬-like proteins TβL1 and TβLR1 that are post-translationally modified with small ubiquitin-like modifiers (SUMOylation). The anti-cancer drug, BC2059 (Tegavivint), has been developed to competitively inhibit interactions between β-catenin and SUMOylated TβL1/TβLR1 and is currently undergoing Phase-I clinical trials. It is currently unknown whether the SUMOylated TβL1/TβLR1 complex mediates β-catenin nuclear translocation in DD. In this study, we investigated whether β-catenin interactions with SUMOylated TβL1/TβLR1 were present in primary fibroblasts derived from patients with DD, and if cytokine treatments mimicking inflammation during fibrosis modified these interactions. Through western blotting, proximity ligation assays, and confocal microscopy, we confirmed that in DD fibroblasts— the levels of SUMOylated TβL1/TβLR1 increased in response to cytokines. Moreover, we observed that the interactions between β-catenin and TβL1/TβLR1 were significantly increased. The novel finding of cytokine-induced SUMOylation of TβL1/TβLR1 presents a mechanistic link between inflammation and fibroproliferation. Given the prevalence and debilitating nature of DD, there exists a need to identify new therapeutic targets to prevent disease progression and recurrence — the results of this study identify SUMOylated TβL1/TβLR1 interactions with β-catenin as a feasible target and provide a strong rationale to cross-purpose anti-cancer drugs such as BC2059 to treat DD.