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Hypoxia-inducible factor 1 (HIF-1) plays a role in tumour metastases; however, the genes that activate HIF-1 and subsequently promote metastases have yet to be identified. Here we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1) abrogates the von Hippel-Lindau-mediated ubiquitination of HIF-1α, the regulatory subunit of HIF-1, and consequently promotes metastasis. The aberrant overexpression of UCHL1 facilitates distant tumour metastases in a HIF-1-dependent manner in murine models of pulmonary metastasis. Meanwhile, blockade of the UCHL1-HIF-1 axis suppresses the formation of metastatic tumours. The expression levels of UCHL1 correlate with those of HIF-1α and are strongly associated with the poor prognosis of breast and lung cancer patients. These results indicate that UCHL1 promotes metastases as a deubiquitinating enzyme for HIF-1α, which justifies exploiting it as a prognostic marker and therapeutic target of cancers.

Original publication

DOI

10.1038/ncomms7153

Type

Journal article

Journal

Nat Commun

Publication Date

23/01/2015

Volume

6

Keywords

Animals, Biomarkers, Tumor, Cell Line, Tumor, Female, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Molecular Targeted Therapy, NIH 3T3 Cells, Neoplasm Metastasis, Neoplasms, Prognosis, Protein Stability, Ubiquitin Thiolesterase, Ubiquitination, Up-Regulation