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Published on: January 20, 2019
EZH2 W113C is a gain-of-function mutation in B-cell lymphoma enabling both PRC2 methyltransferase activation and
Liping Chu1, Dongxia Tan2, Meimei Zhu2
1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China; Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
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.
Insights
A novel EZH2 mutation (W113C) enhances Polycomb repressive complex 2 (PRC2) activity and causes resistance to tazemetostat, a targeted cancer therapy. EED-binding inhibitors effectively target this resistant mutation in lymphoma.
Area of Science:
- Epigenetics and Gene Regulation
- Cancer Biology
- Molecular Oncology
Background:
- Polycomb repressive complex 2 (PRC2) epigenetically silences genes via histone H3 lysine 27 trimethylation (H3K27me3).
- Activating mutations in the EZH2 catalytic subunit, such as Y641, are common in cancers like lymphoma and melanoma, leading to increased H3K27me3 and tumorigenicity.
- Understanding PRC2 regulation and resistance mechanisms is crucial for developing effective cancer therapies.
Purpose of the Study:
- To identify novel gain-of-function mutations in EZH2 outside the catalytic SET domain.
- To investigate the functional consequences of the identified W113C mutation on PRC2 activity, H3K27me3 levels, and tumor suppressor gene silencing.
- To evaluate the efficacy of existing and alternative PRC2 inhibitors against EZH2 W113C-driven resistance.
Main Methods:
- Analysis of EZH2 mutations in lymphoma patient data from cancer genome databases.
- In vitro and in vivo biochemical assays to assess H3K27 methylation activity of wild-type and mutant EZH2.
- Cellular assays to measure CDKN2A silencing and tumor proliferation rates.
- Drug sensitivity testing using tazemetostat and EED-binding inhibitors in cells harboring the EZH2 W113C mutation.
Main Results:
- A novel gain-of-function EZH2 mutation, W113C, was identified in lymphoma patients.
- The W113C mutation increases H3K27me3 levels and silences the CDKN2A gene, similar to the known Y641F mutation.
- EZH2 W113C confers resistance to the EZH2 inhibitor tazemetostat, but remains sensitive to allosteric PRC2 inhibitors targeting EED.
- The W113C mutation is located in the SET-activation loop, stabilizing the SET domain and enhancing substrate binding.
Conclusions:
- The EZH2 W113C mutation represents a new mechanism of PRC2 activation and contributes to lymphoma development.
- This mutation confers resistance to direct EZH2 inhibitors like tazemetostat, highlighting a clinical challenge.
- Targeting EED with allosteric inhibitors offers a promising therapeutic strategy to overcome resistance mediated by the EZH2 W113C mutation in lymphoma.
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