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

Santanu Adhikary, Deepavali Chakravarti, Christopher Terranova, Isha Sengupta, Mayinuer Maitituoheti, Anirban Dasgupta, Dushyant Kumar Srivastava, Junsheng Ma, Ayush T. Raman, Emily Tarco, Aysegul A. Sahin, Roland Bassett, Fei Yang, Coya Tapia, Siddhartha Roy, Kunal Rai, Chandrima Das

    Research output: Contribution to journalArticlepeer-review

    38 Scopus citations

    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.

    Original languageEnglish (US)
    Article number1398
    JournalNature Communications
    Volume10
    Issue number1
    DOIs
    StatePublished - Dec 1 2019

    ASJC Scopus subject areas

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Physics and Astronomy(all)

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