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

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 and Ruey-Hwa Chen ()
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Hsin-Chieh Wu: Graduate Institute of Life Sciences, National Defense Medical Center
Yu-Ching Lin: Institute of Biological Chemistry, Academia Sinica
Cheng-Hsin Liu: Institute of Biological Chemistry, Academia Sinica
Hsiang-Ching Chung: Institute of Biological Chemistry, Academia Sinica
Ya-Ting Wang: Institute of Biological Chemistry, Academia Sinica
Ya-Wen Lin: Graduate Institute of Life Sciences, National Defense Medical Center
Hsin-I. Ma: Graduate Institute of Life Sciences, National Defense Medical Center
Pang-Hsien Tu: Institute of Biomedical Sciences, Academia Sinica
Sean E. Lawler: Brigham and Women’s Hospital, Harvard Medical School
Ruey-Hwa Chen: Graduate Institute of Life Sciences, National Defense Medical Center

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4214

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