# The Kdm6a-dependent Sex Epigenome in Bladder Tumor Suppression

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $541,082

## Abstract

PROJECT 3 – PROJECT SUMMARY
Sex differences in bladder cancer (BC)—men being 3-5 times more likely to have BC than women—are a long-
standing clinical observation. Such disparities persist across socioeconomic and geographic strata even when
correcting for known hazards such as smoking and other environmental risks. Yet despite many years of
research, the etiology of BC sex differences, especially as it relates to sex as a biological variable (SABV),
remains ill-defined. Using “four-core genotypes” mice that consist of four instead of two sex types, we identified
a prototypical sex-biasing tumor suppressor in females: histone lysine demethylase 6A (KDM6A, aka UTX). The
X-linked KDM6A encodes a potent epigenetic regulator that expresses twice as high in females as in males due
to its escape from X-chromosome inactivation. Consistently, somatic mutations of human KDM6A, frequently
observed in BC patients of both sexes, are correlated with poor outcomes in females but not in males. We further
showed that the X chromosome has both an independent and interactive sex-biasing effects with sex hormone
pathways. Based on the published and preliminary findings, we hypothesize that sex differences in BC stems
from effects of the sex chromosome linked epigenetic regulators (i.e., KDM6A and UTY) and effects of the sex
hormones (i.e., androgens and estrogens), collectively shaping a sex specific epigenetic landscape in the
bladder and sex specific immune tumor microenvironment. We will test this hypothesis with three aims: 1)
compare the function of Y-linked UTY in males with its paralog X-linked KDM6A to determine whether UTY also
plays a tumor suppressor role in vivo; 2) determine whether KDM6A, UTY, and sex hormones collectively shape
the epigenetic landscape to drive sex differences in BC; 3) elucidate the mechanism through which KDM6A
differentially modulates pro-tumorigenic immune microenvironment in the bladder. The long-term objectives of
this proposal are two-fold: (1) identify key epigenetic and immune pathways that modulate sex-specific bladder
tumorigenesis and (2) translate mechanistic discoveries to clinical improvement in BC screening and treatment
for males and females.

## Key facts

- **NIH application ID:** 10629080
- **Project number:** 1P01CA278732-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Xue Sean Li
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $541,082
- **Award type:** 1
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10629080

## Citation

> US National Institutes of Health, RePORTER application 10629080, The Kdm6a-dependent Sex Epigenome in Bladder Tumor Suppression (1P01CA278732-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10629080. Licensed CC0.

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