USP11 regulates PML stability to control Notch-induced malignancy in brain tumours.
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.
1] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan [2] Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Hsin-Chieh
HC
Wu
1] Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan [2] Institute of Biochemical Sciences, National Taiwan University, Taipei 100, Taiwan.
Yu-Ching
YC
Lin
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Cheng-Hsin
CH
Liu
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Hsiang-Ching
HC
Chung
1] Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan [2] Institute of Biochemical Sciences, National Taiwan University, Taipei 100, Taiwan.
Ya-Ting
YT
Wang
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.
Ya-Wen
YW
Lin
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.
Hsin-I
HI
Ma
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Pang-Hsien
PH
Tu
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sean E
SE
Lawler
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.
Ruey-Hwa
RH
Chen
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D051880:Receptors, Notch / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D051880:Receptors, Notch; D013869:Thiolester Hydrolases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C485631:HEY1 protein, human; C101359:USP11 protein, human; C070576:PML protein, human