RT Journal Article
SR Electronic
T1 TRAF4 inhibits bladder cancer progression by promoting BMP/SMAD signalling pathway
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.12.335588
DO 10.1101/2020.10.12.335588
A1 Prasanna Vasudevan Iyengar
A1 Dieuwke Louise Marvin
A1 Dilraj Lama
A1 Tuan Zea Tan
A1 Sudha Suriyamurthy
A1 Feng Xie
A1 Maarten van Dinther
A1 Hailiang Mei
A1 Chandra Shekhar Verma
A1 Long Zhang
A1 Laila Ritsma
A1 Peter ten Dijke
YR 2020
UL http://biorxiv.org/content/early/2020/10/12/2020.10.12.335588.abstract
AB Bladder cancer is one of the most prevalent cancer types in the world, frequently exhibiting invasion and metastasis and therefore associated with poor prognosis. It is a progressive disease with high recurrence rates even after surgery, which calls for the urgent need for early intervention and diagnosis. The E3 ubiquitin ligase TNF Receptor Associated Factor 4 (TRAF4) has been largely implicated as a tumour-promoting element in a wide range of cancers. Over-expression and amplification of this gene product has been a common observation in breast and other metastatic tumours. In contrast, we observed that expression of TRAF4 negatively correlated with overall patient survival. Moreover, its expression was repressed at epigenetic levels in aggressive bladder cancer cells. We also describe an ERK kinase phosphorylation site on TRAF4 that inhibits its stability and localization to plasma membrane in such cells. Furthermore, knockdown of TRAF4 in epithelial bladder cancer cell lines leads to gain of mesenchymal genes and a loss of epithelial integrity. Reciprocally, stable over-expression of TRAF4 in mesenchymal cells leads to decreased migratory and invasive properties. Transcriptomic analysis upon TRAF4 mis-expression in bladder cancer cell lines revealed that higher TRAF4 expression enhanced BMP/SMAD and dampened NF-κB signalling pathways. Importantly, this notion was confirmed in bladder cancer patient material. Mechanistically, we showed that TRAF4 targets the E3 ubiquitin ligase SMURF1, a negative regulator of BMP/SMAD signalling, for proteasomal degradation in bladder cancer cells. We show that genetic and pharmacological inhibition of SMURF1 or its function inhibited migration of aggressive (mesenchymal) bladder cancer cells.Competing Interest StatementThe authors have declared no competing interest.