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

Award Number: R01CA266861
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/12/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $303,682 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Cause and Prevention Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$303,682
														Subtotal = $303,682

Issue Date FY: 2025 ( Subtotal = $337,425 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Cause and Prevention Research	000	3	12/10/2024	NON-COMPETING CONTINUATION	$303,682
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Cause and Prevention Research	001	3	6/9/2025	NON-COMPETING CONTINUATION	$33,743
														Subtotal = $337,425

Issue Date FY: 2024 ( Subtotal = $320,554 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Cause and Prevention Research	001	2	4/22/2024	NON-COMPETING CONTINUATION	$16,872
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Cause and Prevention Research	000	2	12/11/2023	NON-COMPETING CONTINUATION	$303,682
														Subtotal = $320,554

Issue Date FY: 2023 ( Subtotal = $337,425 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Cause and Prevention Research	001	1	2/3/2023	NEW	$0
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Cause and Prevention Research	000	1	1/12/2023	NEW	$337,425
														Subtotal = $337,425

Grand Total All Awards = $1,299,086

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

Award Number: R01CA266861

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/12/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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