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Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor

Author

Listed:
  • Santanu Adhikary

    (Saha Institute of Nuclear Physics
    CSIR-Indian Institute of Chemical Biology)

  • Deepavali Chakravarti

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Christopher Terranova

    (The University of Texas MD Anderson Cancer Center)

  • Isha Sengupta

    (Saha Institute of Nuclear Physics)

  • Mayinuer Maitituoheti

    (The University of Texas MD Anderson Cancer Center)

  • Anirban Dasgupta

    (CSIR-Indian Institute of Chemical Biology)

  • Dushyant Kumar Srivastava

    (CSIR-Indian Institute of Chemical Biology)

  • Junsheng Ma

    (The University of Texas MD Anderson Cancer Center)

  • Ayush T. Raman

    (The University of Texas MD Anderson Cancer Center)

  • Emily Tarco

    (The University of Texas MD Anderson Cancer Center)

  • Aysegul A. Sahin

    (The University of Texas MD Anderson Cancer Center)

  • Roland Bassett

    (The University of Texas MD Anderson Cancer Center)

  • Fei Yang

    (The University of Texas MD Anderson Cancer Center)

  • Coya Tapia

    (The University of Texas MD Anderson Cancer Center)

  • Siddhartha Roy

    (CSIR-Indian Institute of Chemical Biology)

  • Kunal Rai

    (The University of Texas MD Anderson Cancer Center)

  • Chandrima Das

    (Saha Institute of Nuclear Physics)

Abstract

The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/β-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.

Suggested Citation

  • Santanu Adhikary & Deepavali Chakravarti & Christopher Terranova & Isha Sengupta & Mayinuer Maitituoheti & Anirban Dasgupta & Dushyant Kumar Srivastava & Junsheng Ma & Ayush T. Raman & Emily Tarco & A, 2019. "Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08986-5
    DOI: 10.1038/s41467-019-08986-5
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