# Differential biophysical properties of protein condensates formed by a tumor suppressor contribute to sexual dimorphism in cancer

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2021 · $415,255

## Abstract

PROJECT SUMMARY
It remains incompletely understood why men are more likely to get and die from cancer than
women. Tumor suppressor genes that escape from X-inactivation substantially contribute to the
lower cancer incidence in females. Some of these genes, including UTX/KDM6A, have Y-
chromosome homologs, but human cancer genetics suggest that the Y homologs are less tumor-
suppressive than their X-chromosome counterparts, such that the X-X pairs are more tumor-
suppressive than the X-Y homologs. This activity bias contributes to the cancer sex dimorphism,
but its underlying molecular mechanisms are unknown. In our preliminary studies, we found that
the UTX undergoes liquid-liquid phase separation that is mediated by its core Intrinsically
Disordered Region (cIDR), and this property is critical for its tumor suppressive activity by co-
condensing MLL4 and its H3K4 mono-methylation activity into the same droplets on chromatin
and greatly enhances. We then found that cIDR is the key determinant of the lower tumor
suppressive activity of UTY. UTY cIDR has a stronger propensity than UTX cIDR to form
condensates, but UTY condensates are less dynamic than UTX condensates. Our results allow
us to formulate and further test our central hypothesis that natural variations in the UTX and UTY
condensate properties affect their tumor suppressive activity and contribute to male bias in
cancer.
Specific Aim 1. Determine the contribution of UTY cIDR to its weaker tumor suppressive
activity.
Specific Aim 2: Link the differential condensate properties to differential tumor
suppressive activities through identification of key determinant in UTY cIDR.
These studies will lay foundation for follow-up in-depth studies, which will establish a new concept
that key and variations related to a fundamental principle of cellular organization contribute to the
sexual dimorphisms in cancer incidence.

## Key facts

- **NIH application ID:** 10173111
- **Project number:** 1R21CA257936-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Hao Jiang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,255
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173111

## Citation

> US National Institutes of Health, RePORTER application 10173111, Differential biophysical properties of protein condensates formed by a tumor suppressor contribute to sexual dimorphism in cancer (1R21CA257936-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10173111. Licensed CC0.

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