EZH2 W113C is a gain-of-function mutation in B-cell lymphoma enabling both PRC2 methyltransferase activation and tazemetostat resistance.

Abstract

Polycomb repressive complex 2 (PRC2) suppresses gene transcription by methylating lysine 27 of histone H3 (H3K27) and plays critical roles in embryonic development. Among the core PRC2 subunits, EZH2 is the catalytic subunit and EED allosterically activates EZH2 upon binding trimethylated H3K27 (H3K27me3). Activating mutations on Y641, A677, and A687 within the enzymatic SET (Su(Var)3 to 9, Enhancer-of-zeste, and Trithorax) domain of EZH2 have been associated with enhanced H3K27me3 and tumorigenicity of many cancers including B-cell lymphoma and melanoma. To tackle the critical residues outside the EZH2 SET domain, we examined EZH2 mutations in lymphoma from cancer genome databases and identified a novel gain-of-function mutation W113C, which increases H3K27me3 in vitro and in vivo and promotes CDKN2A silencing to a similar level as EZH2 Y641F. Different from other gain-of-function mutations, this mutation is located in the SET-activation loop at the EZH2 N terminus, which stabilizes the SET domain and facilitates substrate binding. This may explain how the W113C mutation increases PRC2 activity. Tazemetostat is a Food and Drug Administration-approved EZH2-binding inhibitor for follicular lymphoma treatment. Intriguingly, the W113C mutation leads to tazemetostat resistance in both H3K27 methylation and tumor proliferation. Another class of allosteric PRC2 inhibitor binding EED overcomes the resistance, effectively decreases H3K27me3, and blocks tumor proliferation in cells expressing EZH2 W113C. As this mutation is originally identified from lymphoma samples, our results demonstrated its activating characteristic and the deleterious consequence, provide insights on PRC2 regulation, and support the continued exploration of treatment optimization for lymphoma patients.

• Authors: Liping Chu, Dongxia Tan, Meimei Zhu, Yuxiu Qu, Xin Ma, Bao-Liang Song, Wei Qi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 299 Issue 4 Pg. 103073 (04 2023) ISSN: 1083-351X [Electronic] United States
• PMID: 36858198 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Enhancer of Zeste Homolog 2 Protein
• EZH2 protein, human
• Histones
• Polycomb Repressive Complex 2
• tazemetostat

Topics

• Humans
• Enhancer of Zeste Homolog 2 Protein (genetics, metabolism)
• Gain of Function Mutation
• Histones (metabolism)
• Lymphoma, B-Cell (drug therapy, genetics)
• Mutation
• Polycomb Repressive Complex 2 (genetics)
• Drug Resistance, Neoplasm