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SMYD3 regulates gastric cancer progression and macrophage polarization through EZH2 methylation

Cancer Gene Therapy volume 30, pages 575–581 (2023)Cite this article

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Abstract

SET and MYND domain-containing protein 3 (SMYD3), a known histone methyltransferase, was reported to regulate cancer pathogenesis. However, its role in gastric development and progression remains unclear. EZH2 methylation had been associated with cancer metastasis, but the EZH2 methylation status in gastric cancer (GC) is unknown. Here, we report that EZH2 K421 methylation was responsible for gastric cancer cell soft agar colony formation, in vivo metastasis, and macrophage polarization. Mechanically, we identified SMYD3 as the methyltransferase of EZH2 at K421 residue which accelerates EZH2 Ubiquitin proteasome degradation. Cell harboring non-methylated EZH2 mutants promotes gastric cancer cell metastasis. Taken together, our results showed that SMYD3-EZH2 axis restricts gastric cancer metastasis via integrating epigenetic signaling.

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Fig. 1: EZH2 methylation and clinical features.
Fig. 2: EZH2 K421me1 promotes gastric cancer growth and metastasis in vitro.
Fig. 3: EZH2 K421me1 promotes gastric cancer growth and metastasis in vivo.
Fig. 4: EZH2 K421me1 promotes M2 macrophage polarization.
Fig. 5: SMYD3 mediates EZH2 methylation in gastric cancer cells.
Fig. 6: SMYD3 loss aggravates gastric cancer progression through EZH2 methylation.
Fig. 7: SMYD3-Mediated K421me1 promotes EZH2 degradation.

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All data generated or analyzed are submitted to the journal.

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Funding

This work was supported by grants from Jiangsu Cadre health care research project fund (BJ16008) and Jiangsu Province Science and Technology Department (BE2018698). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Peng Wang, Liang Zhao.

Authors and Affiliations

  1. Department of General Surgery, The Affiliated Geriatric Hospital of Nanjing Medical University, 65 Jiangsu Road, Nanjing, Jiangsu Province, China

    Peng Wang, Yiqi Rui & Yongbin Ding

  2. Department of General Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. No.1 ZhongFu Road, Gulou District, Nanjing, 210006, China

    Liang Zhao

  3. Department of General Surgery, Pukou Branch of Jiangsu People’s Hospital, Nanjing, China

    Yongbin Ding

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Contributions

PW: data curation, roles/writing-original draft, and funding acquisition. LZ, YR: data curation and methodology. PW: methodology and writing-review and editing. PW: conceptualization and writing-review and editing. All authors read and approved the final manuscript.

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Correspondence to Peng Wang or Yongbin Ding.

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The collection of human tissues was approved by the Ethics Committee of Nanjing PuKou Central Hospital. Sixty patients diagnosed with GC were recruited and signed informed consent to participate in this study. Animal protocols were designed following the guideline and received approval from the Institutional Animal Care and Use Committee of Nanjing Pukou Central Hospital.

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Wang, P., Zhao, L., Rui, Y. et al. SMYD3 regulates gastric cancer progression and macrophage polarization through EZH2 methylation. Cancer Gene Ther 30, 575–581 (2023). https://doi.org/10.1038/s41417-022-00535-5

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