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Gli1‐induced deubiquitinase USP 48 aids glioblastoma tumorigenesis by stabilizing Gli1
Author(s) -
Zhou Aidong,
Lin Kangyu,
Zhang Sicong,
Ma Li,
Xue Jianfei,
Morris SaintAaron,
Aldape Kenneth D,
Huang Suyun
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643124
Subject(s) - gli1 , carcinogenesis , hedgehog , deubiquitinating enzyme , cancer research , hedgehog signaling pathway , cell growth , transcription factor , biology , cyclopamine , gene knockdown , signal transduction , microbiology and biotechnology , ubiquitin , apoptosis , cancer , genetics , gene
Aberrant activation of the Hedgehog (Hh) signaling pathway drives the tumorigenesis of multiple cancers. In this study, we screened a panel of deubiquitinases that may regulate the Hh pathway. We find that deubiquitinase USP 48 activates Gli‐dependent transcription by stabilizing Gli1 protein. Mechanistically, USP 48 interacts with Gli1 and cleaves its ubiquitin off directly. In glioblastoma cells, knockdown of USP 48 inhibits cell proliferation and the expression of Gli1's downstream targets, which leads to repressed glioblastoma tumorigenesis. Importantly, USP 48's effect on cell proliferation and tumorigenesis depends to some extent on Gli1. In addition, we find that the Sonic Hedgehog ( SHH ) pathway induces USP 48 expression through Gli1‐mediated transcriptional activation, which forms thus a positive feedback loop to regulate Hh signaling. In human glioblastoma specimens, the expression levels of USP 48 and Gli1 proteins are clinically relevant, and high expression of USP 48 correlates with glioma malignancy. In summary, our study reveals that the USP 48‐Gli1 regulatory axis is critical for glioma cell proliferation and glioblastoma tumorigenesis.