USP11 Regulates PML Stability to Control Notch-induced Malignancy in Brain Tumours

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Feb 4

PMID 24487962

Citations 60

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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