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.
Mesh Terms:
Basic Helix-Loop-Helix Transcription Factors, Brain Neoplasms, Cell Cycle Proteins, Gene Expression Regulation, Neoplastic, Glioblastoma, HeLa Cells, Humans, Nuclear Proteins, Receptors, Notch, Thiolester Hydrolases, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
Nat Commun
Date: Feb. 04, 2014
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