HDAC4 overexpression predicts aggressive phenotypes and poor outcomes in urothelial carcinoma

• Up-regulated expression of HDAC4 positively correlated with aggressive pathological characteristics, including advanced tumor stage, nodal metastases, high tumor grade and mitotic rate, and vascular/perineural invasion. • HDAC4 expression is significantly associated with disease-specific survival (DSS) and metastasis-free survival (MFS), as well as demonstrated as an independent factor of predicting oncological outcomes. • HDAC4 is considered a promising therapeutic target for treating UC. Background: Aberrant epigenetic regulation contributes to cancer progression. Transcriptome profiling of bladder urothelial carcinoma (UBUC) (GSE31684) revealed that HDAC4 upregulation is associated with metastasis. However, its prognostic value in urothelial carcinoma (UC) remains unclear. This study aimed to evaluate the clinical significance of HDAC4 expression in UC. Patients and Methods: Tumor specimens from 340 upper tract UC (UTUC) and 295 UBUC patients were collected. HDAC4 expression was assessed via immunohistochemistry and quantified using H-score. Associations with clinicopathological features and survival outcomes, including disease-specific survival (DSS) and metastasis-free survival (MFS), were analyzed using Chi-square test, Kaplan–Meier analysis, and multivariate Cox regression. Results: HDAC4 expression was elevated in invasive and metastatic UC tissues. High HDAC4 expression correlated with advanced pT stage, nodal metastasis, high tumor grade, vascular/perineural invasion, and high mitotic activity in both UTUC and UBUC. Kaplan–Meier analysis showed that high HDAC4 expression was significantly associated with poorer DSS and MFS in both cohorts (all P < 0.001). Multivariate analysis identified HDAC4 overexpression as an independent predictor of shorter DSS (HR 3.180, P = 0.015) and MFS (HR 6.038, P < 0.001) in UTUC, and shorter MFS (HR 2.279, P = 0.003) in UBUC. Conclusion: HDAC4 overexpression is significantly associated with aggressive clinicopathological features and worse outcomes in UC, highlighting its potential as both a prognostic biomarker and a therapeutic target.