# Sexual Dimorphism in Bladder Cancer

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $592,550

## Abstract

Bladder cancer (BCa) exhibits a striking sex bias: men are 3-5 times more likely than women to develop and die
from BCa. Even when known risk factors such as smoking, infection, occupational hazards, cultural and
environmental factors are corrected for, this phenomenon persists. Despite this long-standing clinical observation,
men and women still receive relatively similar treatments due to a lack of mechanistic understanding to derive
useful treatments based on biological sex. In this proposal, we seek to elucidate the mechanistic basis of sexual
dimorphism in tumor biology. It is well established that gonadal hormone effects (GHE), defined by gonad-
derived hormonal factors that drive sex disparities in BCa, are primarily mediated by male dominant androgens
and androgen receptor (AR). Recently, we reported an unexpected sex chromosome effect (SCE) that
independently contributes to the sexual dimorphism of BCa; we found that SCE is predominantly mediated by
lysine (K) demethylase 6a (KDM6A), which functions as a female-biased tumor suppressor gene in the bladder.
KDM6A demethylase is a versatile epigenetic regulator that controls histone methylations in both enzymatic
activity development and independent mechanisms. We will refer the sex-specific epigenome to as the sex
epigenome. We hypothesize that the sex epigenome, programed by KDM6A directly and AR indirectly, controls
sexual dimorphism in gene expression and BCa. We designed three specific aims to test this hypothesis: 1) to
determine whether KDM6A shapes directly the sex epigenome and regulates the local bioavailability of sex
hormones in the bladder; 2) to determine whether AR opposes the KDM6A-dependent sex epigenome in the
bladder; and 3) to determine whether the sex epigenome differentially regulates genes during bladder
carcinogenesis. Success of the proposal will catalyze the identification of sex-biased genes and regulatory
elements for the design of sex-specific BCa screening and treatment. Results from our proposed studies will
also advance the mechanistic understanding behind greater BCa incidence in males and lead future efforts to
prevent and treat BCa according to a patient's biological sex. Because male dominance in cancer incidence and
mortality is observed across most non-reproductive cancer types, an improved understanding of sexual
dimorphism in BCa will also have widespread implications on these cancers.

## Key facts

- **NIH application ID:** 10674879
- **Project number:** 5R01CA267108-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Xue Sean Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $592,550
- **Award type:** 5
- **Project period:** 2022-08-02 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10674879

## Citation

> US National Institutes of Health, RePORTER application 10674879, Sexual Dimorphism in Bladder Cancer (5R01CA267108-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10674879. Licensed CC0.

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