The epithelial–mesenchymal transition (EMT) and subsequent muscle invasion and metastasis underlie poor patient outcomes in bladder cancer, and molecular mechanisms facilitating EMT in bladder cancer require further interrogation. In their study on page 1516, Iyengar and colleagues investigate the role of tumor necrosis factor receptor-associated factor 4 (TRAF4)—an E3 ubiquitin ligase previously ascribed with oncogenic functions—in bladder cancer and show for the first time that TRAF4 is a tumor suppressor in the disease. The authors found that TRAF4 negatively correlates with EMT scores and disease staging, and that TRAF4 expression is ablated by encoding DNA methylation and ERK-mediated phosphorylation and degradation. Mechanistically, TRAF4 negatively correlates with NF-κB signaling and targets and degrades Smad ubiquitination regulatory factor 1 (SMURF1), another E3 ubiquitin ligase that targets bone morphogenetic protein (BMP)/SMAD signaling and promotes EMT. The cover depicts fluorescent immunohistochemical TRAF4 detection using a stage I bladder cancer tissue microarray sample. This article is also Highlighted on page 1469.