Project description:The UTX/KDM6A gene encodes the UTX histone H3K27 demethylase, which plays an important role in mammalian development and is frequently mutated in cancers and particularly, in urothelial cancers. Using BioID technique, we explored the interactome of different UTX isoforms.
Project description: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.
Project description:Large-scale genome sequencing efforts of human tumors identified epigenetic modifiers as one of the most frequently mutated gene class in human cancer. However, how these mutations drive tumor development and progression is largely unknown. Here, we identify the histone demethylase KDM6A as an important tumor suppressor in solid cancers, such as liver cancer and pancreatic cancer. KDM6A-deficient tumors show hyperactivation of mTORC1 signaling, whereas endogenous KDM6A re-expression in established KDM6A-deficient tumors diminishes mTORC1 activity by fostering the expression of crucial negative pathway regulators, such as DEPTOR, TSC1, and TSC2, resulting in tumor regression. Importantly, KDM6A expression in human tumors correlates with mTORC1 activity and KDM6A-deficient tumors exhibit increased sensitivity to mTORC1 inhibition. Hence, our results link KDM6A-dependent epigenetic remodeling to mTORC1 signaling and provide a potential therapeutic strategy for KDM6A-deficient tumors.
Project description:In this study, we used conditional knockout and gene expression approaches to understand global molecular and transciptional changes due to ablation of each integrin subunit. Affymetrix MoGene-2_0-st-v1 gene chip
