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

Nat Commun

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.

Published: October 2015

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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645609PMC
http://dx.doi.org/10.1038/ncomms4214DOI Listing

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