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USP11 regulates PML stability to control Notch-induced malignancy in brain tumours

Author

Listed:
  • Hsin-Chieh Wu

    (Graduate Institute of Life Sciences, National Defense Medical Center
    Institute of Biological Chemistry, Academia Sinica)

  • Yu-Ching Lin

    (Institute of Biological Chemistry, Academia Sinica
    Institute of Biochemical Sciences, National Taiwan University)

  • Cheng-Hsin Liu

    (Institute of Biological Chemistry, Academia Sinica)

  • Hsiang-Ching Chung

    (Institute of Biological Chemistry, Academia Sinica)

  • Ya-Ting Wang

    (Institute of Biological Chemistry, Academia Sinica
    Institute of Biochemical Sciences, National Taiwan University)

  • Ya-Wen Lin

    (Graduate Institute of Life Sciences, National Defense Medical Center
    National Defense Medical Center)

  • Hsin-I. Ma

    (Graduate Institute of Life Sciences, National Defense Medical Center
    Tri-service General Hospital)

  • Pang-Hsien Tu

    (Institute of Biomedical Sciences, Academia Sinica)

  • Sean E. Lawler

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Ruey-Hwa Chen

    (Graduate Institute of Life Sciences, National Defense Medical Center
    Institute of Biological Chemistry, Academia Sinica
    Institute of Biochemical Sciences, National Taiwan University)

Abstract

The promyelocytic leukaemia (PML) protein controls multiple tumour suppressive functions and is downregulated in diverse types of human cancers through incompletely characterized post-translational mechanisms. Here we identify USP11 as a PML regulator by RNAi screening. USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20–Cul3 (Cullin 3)–Roc1 complex. We find that USP11 is transcriptionally repressed through a Notch/Hey1-dependent mechanism, leading to PML destabilization. In human glioma, Hey1 upregulation correlates with USP11 and PML downregulation and with high-grade malignancy. The Notch/Hey1-induced downregulation of USP11 and PML not only confers multiple malignant characteristics of aggressive glioma, including proliferation, invasiveness and tumour growth in an orthotopic mouse model, but also potentiates self-renewal, tumour-forming capacity and therapeutic resistance of patient-derived glioma-initiating cells. Our study uncovers a PML degradation mechanism through Notch/Hey1-induced repression of the PML deubiquitinase USP11 and suggests an important role for this pathway in brain tumour pathogenesis.

Suggested Citation

  • Hsin-Chieh Wu & Yu-Ching Lin & Cheng-Hsin Liu & Hsiang-Ching Chung & Ya-Ting Wang & Ya-Wen Lin & Hsin-I. Ma & Pang-Hsien Tu & Sean E. Lawler & Ruey-Hwa Chen, 2014. "USP11 regulates PML stability to control Notch-induced malignancy in brain tumours," Nature Communications, Nature, vol. 5(1), pages 1-16, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4214
    DOI: 10.1038/ncomms4214
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    Cited by:

    1. Shirong Deng & Jie Chen & Huidong Shi, 2021. "Integrative analysis of multiple types of genomic data using an accelerated failure time frailty model," Computational Statistics, Springer, vol. 36(2), pages 1499-1532, June.

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