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UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α

By Yoko Goto, Lihua Zeng, Chan Joo Yeom, Yuxi Zhu, Akiyo Morinibu, Kazumi Shinomiya, Minoru Kobayashi, Kiichi Hirota, Satoshi Itasaka, Michio Yoshimura, Keiji Tanimoto, Masae Torii, Terumasa Sowa, Toshi Menju, Makoto Sonobe, Hideaki Kakeya, Masakazu Toi, Hiroshi Date, Ester M. Hammond, Masahiro Hiraoka and Hiroshi Harada


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

Topics: Biological sciences, Cancer
Publisher: Nature Publishing Group
Year: 2015
DOI identifier: 10.1038/ncomms7153
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