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USP11 regulates PML stability to control Notch-induced malignancy in brain tumours.
Wu, Hsin-Chieh; Lin, Yu-Ching; Liu, Cheng-Hsin; Chung, Hsiang-Ching; Wang, Ya-Ting; Lin, Ya-Wen; Ma, Hsin-I; Tu, Pang-Hsien; Lawler, Sean E; Chen, Ruey-Hwa.
Affiliation
  • Wu HC; 1] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan [2] Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
  • Lin YC; 1] Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan [2] Institute of Biochemical Sciences, National Taiwan University, Taipei 100, Taiwan.
  • Liu CH; Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
  • Chung HC; Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
  • Wang YT; 1] Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan [2] Institute of Biochemical Sciences, National Taiwan University, Taipei 100, Taiwan.
  • Lin YW; 1] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan [2] Department of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan.
  • Ma HI; 1] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan [2] Department of Neurological Surgery, Tri-service General Hospital, Taipei 114, Taiwan.
  • Tu PH; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
  • Lawler SE; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • Chen RH; 1] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan [2] Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan [3] Institute of Biochemical Sciences, National Taiwan University, Taipei 100, Taiwan.
Nat Commun ; 5: 3214, 2014.
Article in En | MEDLINE | ID: mdl-24487962
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Thiolester Hydrolases / Transcription Factors / Brain Neoplasms / Nuclear Proteins / Glioblastoma / Cell Cycle Proteins / Tumor Suppressor Proteins / Basic Helix-Loop-Helix Transcription Factors / Receptors, Notch Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2014 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Thiolester Hydrolases / Transcription Factors / Brain Neoplasms / Nuclear Proteins / Glioblastoma / Cell Cycle Proteins / Tumor Suppressor Proteins / Basic Helix-Loop-Helix Transcription Factors / Receptors, Notch Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2014 Document type: Article Affiliation country: