# Project 1: Role of the H3K27 demethylase KDM6A in bladder cancer pathogenesis

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $391,906

## Abstract

Project Summary/Abstract:
 Almost all bladder cancers harbor mutations in genes involved in the regulation of chromatin state.
KDM6A is among the most commonly mutated of these chromatin-modifying genes in urothelial cancers, and
KDM6A alterations are by far more common in urothelial cancer than in any other human cancer type. Here,
we seek to further elucidate the biologic role of KDM6A inactivation in bladder cancer pathogenesis as a
prelude to the development of rational therapeutic strategies for patients with KDM6A mutant urothelial
cancers. On the basis of preliminary data derived from studies of KDM6A isogenic urothelial cancer cells
generated by CRISPR/Cas9-targeted inactivation, we hypothesize that KDM6A inactivation is an early event
in bladder cancer pathogenesis that promotes tumor formation by deregulating genes that play key roles in
modulating RAS/MAP kinase signaling. This proposal will seek to leverage recent advances in next-generation
sequencing, clonality analysis, CRISPR gene editing, and patient-derived organoid and genetically-engineered
mouse (GEMM) modeling to generate cellular and murine models of KDM6A-deficient bladder cancer that
more accurately mirror the genomic profile, histology, and biologic properties of the human disease. These
models and a unique cohort of clinically annotated human bladder cancers and the expertise of our co-
investigators on this Program Project will then be used to perform in-depth analyses of the biology and
functions of KDM6A in bladder cancer pathogenesis. Specifically, we will define the timing at which KDM6A
alterations arise in bladder cancer (Aim 1); explore the biologic mechanisms whereby KDM6A loss promotes
the transformed phenotype and their implications for drug response (Aim 2); and develop oncogene- and
carcinogen-induced mouse models of bladder cancer with Kdm6a loss-of-function to study the mechanisms by
which KDM6A inactivation promotes tumor initiation and/or progression in vivo (Aim 3). A long-term
translational goal of this work will be to use the insights gained from studies of KDM6A mutant tumors and cell
line, organoid and animal models to guide the development of novel therapeutic approaches.
 Integration: The proposed studies are highly complementary with Project 2, which is focused on the
chromatin remodeling gene ARID1A, which is often co-altered in bladder cancers with KDM6A, and with
Project 3, which is studying cancer evolution, heterogeneity, and drug response in novel patient-derived
organoid models, several of which harbor KDM6A mutations. The success of this project will require close
collaboration with all three Cores. Specifically, Core A will provide assistance with the processing and analysis
of human tumors for Aim 1 and aid in the histologic and molecular characterization of bladder tumors that arise
in GEMMs in Aim 3; Core B will provide KDM6A mutant and wildtype human organoid cell lines for Aim 2 and
assist with the generation of GEMMs with targeted...

## Key facts

- **NIH application ID:** 9972889
- **Project number:** 5P01CA221757-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** David B. Solit
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,906
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972889

## Citation

> US National Institutes of Health, RePORTER application 9972889, Project 1: Role of the H3K27 demethylase KDM6A in bladder cancer pathogenesis (5P01CA221757-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972889. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*