Integrative multi-omics analysis reveals a GALNT6/Smad2/CDC7 axis promoting cisplatin resistance through enhanced DNA damage repair in bladder cancer.

Authors

Yang Liu, Ziming Bian, Jianting Hu, Yuanxin Xie, Guanyu Cheng, Yan Zhang, Sairong Fan, Xiaoming Chen

Published in

Functional & integrative genomics. Volume 26. Issue 1. Nov 03, 2026. Epub Nov 03, 2026.

Abstract

Cisplatin-based neoadjuvant chemotherapy remains an important treatment for advanced bladder cancer (BLCA), yet approximately half of patients derive limited benefit because of chemoresistance. Although DNA damage repair (DDR) is a key determinant of this resistance, how DDR heterogeneity contributes to chemoresistance remains unclear. Single-cell transcriptomic analysis revealed DDR heterogeneity among BLCA epithelial cells, with epithelial cells exhibiting higher DDR activity showing greater malignant potential. Bulk transcriptomic and proteomic analyses identified two molecular subtypes of BLCA. Compared with the DDR-Base subtype, the DDR-Active subtype exhibited enhanced DDR function and worse clinical outcomes. Integrative machine-learning modeling and SHapley Additive exPlanations (SHAP) prioritized GALNT6 as a glycosylation-related regulator associated with the DDR-Active phenotype. GALNT6 was highly expressed in the DDR-Active subtype and progressively increased along the epithelial-cell trajectory toward the DDR-enhanced malignant state. Functionally, GALNT6 knockdown impaired DNA damage repair efficiency, thereby overcoming cisplatin resistance in BLCA. Mechanistically, GALNT6 stabilized SMAD2 through O-glycosylation, after which SMAD2 transcriptionally activated CDC7 to enhance repair capacity against exogenous DNA damage. Moreover, GALNT6 and SMAD2 co-expression was a hallmark of the DDR-Active subtype and was associated with advanced tumor stage. This study defines clinically relevant DDR subtypes in BLCA and identifies the GALNT6/SMAD2/CDC7 axis as a driver of cisplatin resistance. These findings provide a biological framework for understanding heterogeneity in cisplatin response and for future treatment stratification.

PMID:
42975739
Bibliographic data and abstract were imported from PubMed on 04 Nov 2026.

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