DIXDC1 Promotes Lymphatic Metastasis and Resistance to Cuproptosis in Bladder Cancer Through Mediating DLAT

Vollständiger Abstract

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ABSTRACT Lymph node metastasis (LN) represents a major clinical challenge in bladder cancer (BCa) and is associated with dismal prognosis; however, the underlying molecular drivers remain incompletely understood. Here, we demonstrate that DIX domain‐containing protein 1 (DIXDC1) is significantly upregulated in LN‐metastatic BCa tissues and is associated with unfavorable clinical outcomes. Functionally, DIXDC1 enhances BCa cell migration, invasion, proliferation, and lymph node dissemination in vivo. Mechanistically, DIXDC1 directly binds to dihydrolipoamide S‐acetyltransferase (DLAT), a key enzyme in the tricarboxylic acid cycle and a central effector of cuproptosis. This interaction impedes ubiquitin‐proteasome‐mediated degradation of DLAT, thereby stabilizing DLAT protein levels. Through a DLAT‐dependent pathway, DIXDC1 further augments the mRNA stability of the oncogenes NEK7 and CCNE2 , fueling tumor progression. Importantly, DIXDC1 shields BCa cells from copper‐induced DLAT oligomerization and confers marked resistance to Elesclomol‐Cu (ES‐Cu)‐triggered cuproptosis. Depletion of DIXDC1 profoundly sensitizes tumors to cuproptosis in vivo. Collectively, our study unveils the DIXDC1‐DLAT axis as a pivotal regulator that coordinately drives metastatic progression and suppresses copper‐induced cell death, offering a promising therapeutic target for advanced BCa.