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

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 ()
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Yoko Goto: Kyoto University Graduate School of Medicine
Lihua Zeng: Kyoto University Graduate School of Medicine
Chan Joo Yeom: Kyoto University Graduate School of Medicine
Yuxi Zhu: Kyoto University Graduate School of Medicine
Akiyo Morinibu: Kyoto University Graduate School of Medicine
Kazumi Shinomiya: Kyoto University Graduate School of Medicine
Minoru Kobayashi: Kyoto University Graduate School of Medicine
Kiichi Hirota: Kyoto University Hospital, Kyoto University
Satoshi Itasaka: Kyoto University Graduate School of Medicine
Michio Yoshimura: Kyoto University Graduate School of Medicine
Keiji Tanimoto: Research Institute for Radiation Biology and Medicine, Hiroshima University
Masae Torii: Kyoto University Graduate School of Medicine
Terumasa Sowa: Kyoto University Graduate School of Medicine
Toshi Menju: Kyoto University Graduate School of Medicine
Makoto Sonobe: Kyoto University Graduate School of Medicine
Hideaki Kakeya: Graduate School of Pharmaceutical Sciences, Kyoto University
Masakazu Toi: Kyoto University Graduate School of Medicine
Hiroshi Date: Kyoto University Graduate School of Medicine
Ester M. Hammond: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford
Masahiro Hiraoka: Kyoto University Graduate School of Medicine
Hiroshi Harada: Kyoto University Graduate School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7153

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