USP11 regulates PML stability to control Notch-induced malignancy in brain tumours
View/ Open
Author
Wu, Hsin-Chieh
Lin, Yu-Ching
Liu, Cheng-Hsin
Chung, Hsiang-Ching
Wang, Ya-Ting
Lin, Ya-Wen
Ma, Hsin-I.
Tu, Pang-Hsien
Chen, Ruey-Hwa
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1038/ncomms4214Metadata
Show full item recordCitation
Wu, Hsin-Chieh, 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. 2014. “USP11 regulates PML stability to control Notch-induced malignancy in brain tumours.” Nature Communications 5 (1): 3214. doi:10.1038/ncomms4214. http://dx.doi.org/10.1038/ncomms4214.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645609/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492301
Collections
- HMS Scholarly Articles [17922]
Contact administrator regarding this item (to report mistakes or request changes)