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EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer

Author

Listed:
  • Marita Zoma

    (Institute of Oncology Research (IOR))

  • Laura Curti

    (Institute of Oncology Research (IOR)
    Fondazione Istituto Italiano di Tecnologia (IIT))

  • Dheeraj Shinde

    (Institute of Oncology Research (IOR))

  • Domenico Albino

    (Institute of Oncology Research (IOR))

  • Abhishek Mitra

    (Institute of Oncology Research (IOR))

  • Jacopo Sgrignani

    (Institute for Research in Biomedicine (IRB))

  • Sarah N. Mapelli

    (Institute of Oncology Research (IOR)
    Swiss Institute of Bioinformatics (SIB))

  • Giada Sandrini

    (Institute of Oncology Research (IOR)
    Swiss Institute of Bioinformatics (SIB))

  • Gianluca Civenni

    (Institute of Oncology Research (IOR))

  • Jessica Merulla

    (Institute of Oncology Research (IOR))

  • Giovanna Chiorino

    (Fondazione Edo ed Elvo Tempia Valenta)

  • Paolo Kunderfranco

    (Institute of Oncology Research (IOR)
    Humanitas Research Center)

  • Alessia Cacciatore

    (Institute of Oncology Research (IOR))

  • Aleksandra Kokanovic

    (Institute of Oncology Research (IOR))

  • Andrea Rinaldi

    (Institute of Oncology Research (IOR))

  • Andrea Cavalli

    (Institute for Research in Biomedicine (IRB))

  • Carlo V. Catapano

    (Institute of Oncology Research (IOR))

  • Giuseppina M. Carbone

    (Institute of Oncology Research (IOR))

Abstract

The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer (Pb-Cre4 Pten flox/flox Rosa26-ERG, ERG/PTEN), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers.

Suggested Citation

  • Marita Zoma & Laura Curti & Dheeraj Shinde & Domenico Albino & Abhishek Mitra & Jacopo Sgrignani & Sarah N. Mapelli & Giada Sandrini & Gianluca Civenni & Jessica Merulla & Giovanna Chiorino & Paolo Ku, 2021. "EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24380-6
    DOI: 10.1038/s41467-021-24380-6
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    Cited by:

    1. Alessia Cacciatore & Dheeraj Shinde & Carola Musumeci & Giada Sandrini & Luca Guarrera & Domenico Albino & Gianluca Civenni & Elisa Storelli & Simone Mosole & Elisa Federici & Alessio Fusina & Marta I, 2024. "Epigenome-wide impact of MAT2A sustains the androgen-indifferent state and confers synthetic vulnerability in ERG fusion-positive prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-25, December.

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