Lymph node (LN) metastasis is one of the key prognostic factors in bladder cancer, but its underlying mechanisms remain unclear. Here, we found that elevated expression of WD repeat domain 4 (WDR4) in bladder cancer correlated with worse prognosis. WDR4 can promote the LN metastasis and proliferation of bladder cancer cells. Mechanistic studies showed that WDR4 can promote the nuclear localization of DEAD-box helicase 20 (DDX20) and act as an adaptor to bind DDX20 and Early growth response 1 (Egr1), thereby inhibiting Egr1-promoted transcriptional expression of arrestin beta 2 (ARRB2) and ultimately contributing to the progression of bladder cancer. Immunohistochemical analysis confirmed that WDR4 expression is also an independent predictor of LN metastasis in bladder cancer. Our results reveal a novel mechanism of LN metastasis and progression in bladder cancer and identify WDR4 as a potential therapeutic target for metastatic bladder cancer.

淋巴结（LN）转移是膀胱癌的关键预后因素之一，但其潜在机制仍不清楚。在这里，我们发现膀胱癌中 WD 重复结构域 4 (WDR4) 的表达升高与预后较差相关。WDR4可以促进膀胱癌细胞的淋巴结转移和增殖。机制研究表明，WDR4可以促进DEAD-box解旋酶20（DDX20）的核定位，并作为接头结合DDX20和早期生长反应1（Egr1），从而抑制Egr1促进的视紫红质抑制蛋白β2（ARRB2）的转录表达最终导致膀胱癌的进展。免疫组织化学分析证实，WDR4 表达也是膀胱癌 LN 转移的独立预测因子。我们的结果揭示了膀胱癌淋巴结转移和进展的新机制，并将 WDR4 确定为转移性膀胱癌的潜在治疗靶点。