title: UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α.
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.
authors.affiliation: 1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Goto
authors.affiliation: 1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan [3] Department of Radiation Medicine, Fourth Military Medical University, 17 Changle West Road, Shaanxi 710032, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zeng
authors.affiliation: 1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan.
authors.forename: Chan Joo
authors.initials: CJ
authors.lastname: Yeom
authors.affiliation: 1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan [3] Department of Oncology, First Affiliated Hospital of Chongqing Medical University, No.1 Friendship Road, Yuanjiagang, Chongqing 400016, China.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: 1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Morinibu
authors.affiliation: 1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Shinomiya
authors.affiliation: 1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, Kyoto University, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Hirota
authors.affiliation: Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itasaka
authors.affiliation: Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Yoshimura
authors.affiliation: Department of Radiation Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Hiroshima 734-8553, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Masae
authors.initials: M
authors.lastname: Torii
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Sowa
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sonobe
authors.affiliation: Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Kyoto 606-8501, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kakeya
authors.affiliation: Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
authors.affiliation: Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiraoka
authors.affiliation: 1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan [3] Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Saitama 332-0012, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D055550:Protein Stability; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase