Nerve Growth Factor Signaling Promotes Nuclear Translocation of TRAF4 to Enhance Tumor Stemness and Metastatic Dormancy Via C‐Jun‐mediated IL‐8 Autocrine

Abstract Tumor necrosis factor receptor‐associated factor 4 (TRAF4), an E3 ubiquitin ligase, is frequently overexpressed in tumors. Although its cytoplasmic role in tumor progression is well‐documented, the precise mechanisms underlying its nuclear localization and functional contributions in tumor cells remain elusive. This study demonstrated a positive correlation between the expression of nuclear TRAF4 and both tumor grades and stemness signatures in human cancer tissues. Notably, reduced nuclear TRAF4 led to decreased stemness properties and metastatic dormancy of tumor cells. Conversely, restoring nuclear TRAF4 in TRAF4‐knockout (TRAF4‐KO) cells augmented these cellular capabilities. Within the nucleus, the TRAF domain of TRAF4 interacted with c‐Jun, thereby stimulating its transcriptional activity. This interaction subsequently led to an enhancement of the promoter activity of interleukin‐8 (IL‐8), which is identified as a mediator of nuclear TRAF4‐induced tumor dormancy. Additionally, activation of AKT signaling by nerve growth factor facilitated TRAF4 phosphorylation at Ser242, enhancing its interaction with 14‐3‐3θ and promoting its nuclear translocation. Importantly, pharmacological modulation of TRAF4 nuclear translocation is found to suppress tumor tumorigenicity and metastasis in tumor models. This study highlights the critical role of nuclear TRAF4 in regulating tumor stemness and dormancy, positioning it as a potential therapeutic target for metastatic and refractory cancers.