Loss of KDM6A-mediated genomic instability and metabolic reprogramming regulates response to therapeutic perturbations in bladder cancer

ABSTRACT: Mutations in genes encoding critical epigenetic regulators are frequently noted in bladder cancer, however, the mechanisms by which these alterations impact the therapeutic response remain incompletely understood. Through retrospective analyses of multiple bladder cancer patient cohorts, we identified that loss-of-function mutations in KDM6A, a histone demethylase altered in approximately 26% of advanced bladder cancers, are associated with reduced overall survival following cisplatin-based chemotherapy whereas they correlate with improved outcomes with anti–PD-1/anti–PD-L1 therapy. To elucidate the biological underpinnings of this divergent clinical response, we conducted reverse translational mechanistic studies using human bladder cancer cell lines harboring mutations in KDM6A gene and CRISPR-Cas9–mediated deletion of Kdm6a in murine bladder cancer models. We found that KDM6A deficiency drives cisplatin resistance via increased generation of extrachromosomal circular DNA (eccDNA) carrying oncogenes linked to drug resistance. Additionally, KDM6A directly regulates DNA mismatch and double-strand break repair genes, and its loss impairs these pathways in both human and murine bladder cancer cells. Concurrently, KDM6A loss alters tumor metabolism, suppressing glycolysis and lactate production, which in turn diminishes histone lactylation (H3K9la, H3K18la) in regulatory T cells (Tregs). This leads to decreased expression of key immune-suppressive genes, including Foxp3, Tgfb, and Pdcd1. Consequently, reduced expansion of PD-1hi Tregs enhances the cytotoxic T cell-to-Treg ratio, improving the response to anti-PD-1 therapy in Kdm6a-deficient tumor-bearing mice. Collectively, these findings establish KDM6A as a key epigenetic regulator of genomic integrity and the immunosuppressive tumor microenvironment and provide a mechanistic rationale for utilizing KDM6A mutation status as a predictive biomarker to guide personalized treatment strategies in advanced bladder cancer.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Yun Xiong  

LAB HEAD: Sangeeta Goswami

PROVIDER: PXD065234 | Pride | 2025-12-04

REPOSITORIES: Pride