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Dissecting and targeting noncanonical functions of EZH2 in multiple myeloma via an EZH2 degrader

Oncogene volume 42, pages 994–1009 (2023)Cite this article

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Abstract

Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation-related markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and simultaneous suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2’s both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.

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Fig. 1: Design of EZH2 putative degraders 2-13 and their effect on inducing EZH2 protein degradation in L-363 cells.
Fig. 2: MS177 decreases genomic binding of both EZH2 and H3K27me3 in MM1.S cells.
Fig. 3: EZH2 noncanonically interacts with cMyc and co-localizes with gene activation markers in MM cells.
Fig. 4: MS177 represses both PRC2 and cMyc-related oncogenic nodes.
Fig. 5: MS177 treatment reactivates immune response genes.
Fig. 6: MS177 effectively inhibits the growth of MM cells.
Fig. 7: MS177 suppresses MM tumor growth in vivo.

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Data availability

Genomic dataset of this study, including CUT&RUN and RNA-Seq, have been deposited in NCBI Gene Expression Omnibus (GEO) database under accession code GSE214669. Publicly available datasets used in the work were from NCBI GEO accession numbers GSE36354 (cMyc, MAX, H3K27ac, H3K4me3 and Pol II data in MM1.S cells). Other data supporting the findings of this study are available upon request.

Code availability

We did not use custom code. All software and packages used in this study are listed in Reporting Summary and are publicly available.

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Acknowledgements

We graciously thank the Wang and Jin Laboratory members for helpful discussion and technical support. This work was supported in part by the US National Institutes of Health grants R01CA218600 (to JJ and GGW), R01CA268519 (GGW and JJ) and R01CA230854 (to JJ), an endowed professorship from the Icahn School of Medicine at Mount Sinai (to JJ), and grants/awards from Gabrielle’s Angel Foundation for Cancer Research (to GGW), When Everyone Survives (WES) Leukemia Research Foundation (to GGW) and UNC Lineberger Cancer Center UCRF Stimulus Initiative Grants (to GGW and LC). GGW is an American Cancer Society Research Scholar, a Leukemia and Lymphoma Society Scholar, and an American Society of Hematology Scholar in Basic Science. This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from National Institutes of Health SIG grants 1S10OD025132 and 1S10OD028504. We thank UNC’s facilities, including High-throughput Sequencing Facility (HTSF), Bioinformatics Core, Tissue Culture Facility, Animal Studies Core and UNC Tissue Procurement Facility, for their professional assistance of this work. The cores affiliated to the UNC Cancer Center are supported in part by the UNC Lineberger Comprehensive Cancer Center Core Support Grant P30CA016086.

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  1. These authors contributed equally: Xufen Yu, Jun Wang.

Authors and Affiliations

  1. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Xufen Yu, Anqi Ma, Yudao Shen, Chengwei Zhang, Jing Liu & Jian Jin

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Jun Wang, Weida Gong, Xijuan Liu, Ling Cai & Gang Greg Wang

  3. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Jun Wang & Gang Greg Wang

  4. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Ling Cai

  5. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Gang Greg Wang

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Contributions

JW, XY, AM, YS, CZ and XL led on biological/genomic and chemical biology studies, respectively, under the guidance of GGW and JJ. JW and WG conducted RNA-seq data analysis under the supervision of LC and GGW. JW analyzed the CUT&RUN and ChIP-seq data under the direction of GGW. XY, JW, LC, JL, GGW and JJ analyzed and interpreted experimental data. JJ and GGW conceived the project. JJ and GGW organized and led the study. XY, WJ, GGW and JJ wrote the manuscript with input from all other authors.

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Correspondence to Xufen Yu, Gang Greg Wang or Jian Jin.

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Competing interests

The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc. and Cullinan Oncology, Inc. JJ is a cofounder and equity shareholder in Cullgen, Inc., a scientific cofounder and scientific advisory board member of Onsero Therapeutics, Inc., and a consultant for Cullgen, Inc., EpiCypher, Inc. and Accent Therapeutics, Inc. The other authors declare no competing interests.

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Yu, X., Wang, J., Gong, W. et al. Dissecting and targeting noncanonical functions of EZH2 in multiple myeloma via an EZH2 degrader. Oncogene 42, 994–1009 (2023). https://doi.org/10.1038/s41388-023-02618-5

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