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.

中文翻译：

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TRAF4通过促进BMP / SMAD信号通路抑制膀胱癌的进展

膀胱癌是世界上最普遍的癌症类型之一，经常表现出浸润和转移，因此预后不良。它是一种进行性疾病，即使在手术后也具有很高的复发率，这迫切需要早期干预和诊断。E3泛素连接酶TNF受体相关因子4（TRAF4）已被广泛认为是多种癌症中的促肿瘤成分。在乳腺癌和其他转移性肿瘤中，这种基因产物的过表达和扩增已成为普遍现象。相反，我们观察到TRAF4的表达与患者总体生存率呈负相关。此外，其表达在侵袭性膀胱癌细胞中在表观遗传水平受到抑制。我们还描述了TRAF4上的ERK激酶磷酸化位点，该位点可抑制其稳定性和在此类细胞中定位于质膜。此外，TRAF4在上皮膀胱癌细胞系中的敲低导致间充质基因的获得和上皮完整性的丧失。相应地，间充质细胞中TRAF4的稳定过表达会导致迁移和侵袭性下降。膀胱癌细胞系中TRAF4错表达的转录组学分析显示，较高的TRAF4表达增强BMP / SMAD并抑制NF-κB信号通路。重要的是，这一观点在膀胱癌患者的材料中得到了证实。从机制上讲，我们显示TRAF4靶向E3泛素连接酶SMURF1（BMP / SMAD信号的负调节剂），用于膀胱癌细胞中的蛋白酶体降解。