Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7153
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Funding
- Funding Program for NEXT Generation World-Leading Researchers (NEXT Program) from Japan Society for the Promotion of Science (JSPS), Japan [LS071]
- programme for Precursory Research for Embryonic Science and Technology (PRESTO) from Japan Science and Technology Agency (JST)
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- JSPS
- MEXT, Japan [26293276, 26461886, 26670558, 24659563, 26670555, 25861088, 24791293]
- Kobayashi Foundation for Cancer Research
- Takeda Science Foundation
- Mochida Memorial Foundation
- International Science and Technology Cooperation Project of China [2010DFA31900]
- Sagawa Foundation for the Promotion of Cancer Research
- International Science and Technology Cooperation Project of Japan [2010DFA31900]
- Cancer Research UK [19276] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [26670693, 15K15577, 25861088, 26670555, 24592322, 26461886, 26293276, 24659563, 24791293, 25462457, 26670558, 15K10551, 24592336] Funding Source: KAKEN
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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-1 alpha, 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-1 alpha 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-1 alpha, which justifies exploiting it as a prognostic marker and therapeutic target of cancers.
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