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

了解 EZHIP 和 K27M 癌组蛋白对儿科神经胶质瘤中 PRC2 活性的调节

• 批准号: 10587207
• 负责人: Peter W Lewis
• 金额: $ 33.74万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-12 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587207
• 关键词: Affect; Affinity; Binding; Biochemical; Biochemistry; Biological Assay; Brain; Catalysis; Cell Differentiation process; Cell Proliferation; Cells; Childhood Glioma; Chromatin; Clinical; Complex; CpG Islands; Data; Development; Elements; Ependymoma; Exhibits; Foundations; Future; Gene Expression; Gene Silencing; Genes; Genetic; Genomics; Glioma; Goals; Health; Histone H3; Histones; Human; Investigation; Knowledge; Lysine; Malignant - descriptor; Malignant Neoplasms; Methionine; Methods; Methylation; Molecular; PRC1 Protein; Pathogenesis; Phenotype; Phosphorylation; Play; Polycomb; Positioning Attribute; Post-Translational Protein Processing; Post-Translational Regulation; Posterior Fossa; Prognosis; Proliferating; Proteins; Regulation; Repression; Research Proposals; Residual state; Resistance; Role; Site; Surface; Testing; Therapeutic; Therapeutic Intervention; Tumor Suppressor Genes; Work; antitumor effect; diffuse midline glioma; effective therapy; genome-wide; histone modification; insight; interdisciplinary approach; loss of function mutation; mutant; neoplastic cell; novel; oncohistone; pre-clinical; programs; promoter; recruit; targeted treatment; theories; therapeutic target; tumor; tumorigenesis; tumorigenic

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.

项目总结