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Updated: Jan 13, 2026
Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Loss of KDM6A-mediated genomic instability and metabolic reprogramming regulates response to therapeutic
Pratishtha Singh1, Ranit D'Rozario1, Bidisha Chakraborty1
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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.
Insights
Loss-of-function mutations in KDM6A impact bladder cancer treatment. KDM6A deficiency causes cisplatin resistance but improves anti-PD-1 therapy outcomes, guiding precision medicine.
Area of Science:
- Oncology
- Epigenetics
- Cancer Immunology
Background:
- Epigenetic regulator mutations are frequent in bladder cancer.
- The role of these mutations in therapeutic response is largely unknown.
- KDM6A mutations occur in ~26% of advanced bladder cancers.
Purpose of the Study:
- To investigate the impact of KDM6A mutations on responses to cisplatin chemotherapy and anti-PD-1 therapy in bladder cancer.
- To elucidate the molecular mechanisms underlying KDM6A's influence on therapeutic resistance and sensitivity.
Main Methods:
- Utilized CRISPR-Cas9 gene editing to create KDM6A-deficient murine and human bladder cancer models.
- Analyzed the formation of extrachromosomal circular DNA (eccDNA) and its role in chemoresistance.
- Assessed DNA repair pathways and tumor metabolic reprogramming, including glycolysis and histone lactylation in T cells.
Main Results:
- KDM6A loss-of-function mutations are linked to poor survival with cisplatin but improved outcomes with anti-PD-1 therapy.
- KDM6A deficiency promotes cisplatin resistance via eccDNA formation and impaired DNA repair.
- KDM6A loss alters tumor metabolism, reducing histone lactylation in regulatory T cells and suppressing anti-tumor immunity.
Conclusions:
- KDM6A mutations are critical determinants of therapeutic response in advanced bladder cancer.
- Findings support KDM6A status as a biomarker for guiding precision therapy selection.
- This study provides a mechanistic basis for KDM6A's role in chemoresistance and immunotherapy response.
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