Loss of KDM6A-Mediated Genomic Instability and Metabolic Reprogramming Regulates Response to Therapeutic Perturbations in Bladder Cancer

Authors

Pratishtha Singh
Ranit D'Rozario
Bidisha Chakraborty
Swadhin Meher
Deblina Raychaudhuri
Aminah J Tannir
Yang Li
Anurag Majumdar
Jessalyn Hawkins
Yun Xiong
Philip Lorenzi
Padmanee Sharma
Kadir Akdemir
Patrick Pilie
Abhinav K Jain
Byron Hing Lung Lee
Sangeeta Goswami

Language

English

Publication Date

1-7-2026

Journal

Nature Communications

DOI

10.1038/s41467-025-68132-2

PMID

41501085

PMCID

PMC12877084

PubMedCentral® Posted Date

1-7-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Mutations in epigenetic regulators are common in bladder cancer, yet their impact on therapeutic responses remains unclear. Here, we identify that loss-of-function mutations in KDM6A, a histone demethylase altered in about 26% of advanced bladder cancers, are associated with poor survival after cisplatin chemotherapy, whereas they correlate with improved outcomes with anti-PD-1 therapy. Using CRISPR-Cas9-engineered murine and human bladder cancer models, we show that KDM6A deficiency increases formation of extrachromosomal circular DNA carrying chemoresistance loci, promoting cisplatin resistance. In parallel, KDM6A loss impairs DNA repair and rewires tumor metabolism, reducing glycolysis and lactate output. This metabolic shift diminishes histone lactylation in regulatory T cells, suppressing immunoregulatory genes and limiting expansion of PD-1hi regulatory T cells. Collectively, our findings establish KDM6A mutation as a key regulator of therapeutic responses, providing a foundation for its use in guiding precision therapy in advanced bladder cancer.

Keywords

Urinary Bladder Neoplasms, Animals, Histone Demethylases, Humans, Mice, Genomic Instability, Cell Line, Tumor, Cisplatin, Drug Resistance, Neoplasm, CRISPR-Cas Systems, DNA Repair, Female, Mice, Knockout, Loss of Function Mutation, Histones, Metabolic Reprogramming, Tumour immunology, Tumour biomarkers, Bladder cancer

Published Open-Access

yes

Recommended Citation

Singh, Pratishtha; D'Rozario, Ranit; Chakraborty, Bidisha; et al., "Loss of KDM6A-Mediated Genomic Instability and Metabolic Reprogramming Regulates Response to Therapeutic Perturbations in Bladder Cancer" (2026). Faculty, Staff and Student Publications. 5246.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5246