# Understanding the regulation of PRC2 activity by EZHIP and the K27M oncohistone in pediatric gliomas

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $320,554

## Abstract

PROJECT SUMMARY
Post-translational regulation of histones and other chromatin-associated proteins is a major means by which
gene expression is modulated during normal and malignant development. Polycomb group proteins are essential
for proper development and are frequently altered in human cancers. The Polycomb Repressive Complex 2
(PRC2) functions in a collaborative chromatin-based crosstalk with PRC1 and H3K27me3 to initiate and maintain
gene silencing. We have found that PRC2 catalysis of H3K27me3 is inhibited in pediatric gliomas by two
suspected tumor drivers: histone H3 K27M and EZHIP. Inhibition of PRC2 activity by K27M and EZHIP can result
in aberrant gene expression, cellular differentiation, and cell proliferation. Despite a substantial reduction in
H3K27 methylation levels caused by EZHIP or K27M, our work has revealed residual H3K27me3 at CpG islands
near promoters of known and suspected tumor suppressor genes. Furthermore, evidence suggests that this
residual PRC2 activity plays a critical role in supporting tumorigenesis. This proposal seeks to leverage and
extend our preliminary findings to define the mechanisms by which K27M and EZHIP misregulate PRC2 to
promote tumorigenesis by employing a multi-disciplinary approach that integrates biochemical, genetic, and
genomic methods. Specifically, we will (1) define the role of aberrant PRC2 activity in promoting K27M and
EZHIP-containing tumors, (2) determine the mechanism of targeting PRC2 to CpG islands in gliomas, and (3)
define the mechanism of PRC2 inhibition by EZHIP. Expected results will help us formulate novel theories and
provide crucial mechanistic basis underlying the pathogenesis by oncohistones. The knowledge generated in
the course of this study will motivate future therapeutic efforts for treating pediatric gliomas.

## Key facts

- **NIH application ID:** 10763885
- **Project number:** 5R01CA266861-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Peter W Lewis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $320,554
- **Award type:** 5
- **Project period:** 2023-01-12 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10763885

## Citation

> US National Institutes of Health, RePORTER application 10763885, Understanding the regulation of PRC2 activity by EZHIP and the K27M oncohistone in pediatric gliomas (5R01CA266861-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10763885. Licensed CC0.

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