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

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-1?, 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? 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?, which justifies exploiting it as a prognostic marker and therapeutic target of cancers.

SUBMITTER: Goto Y

PROVIDER: S-EPMC4317501 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Goto Yoko Y Zeng Lihua L Yeom Chan Joo CJ Zhu Yuxi Y Morinibu Akiyo A Shinomiya Kazumi K Kobayashi Minoru M Hirota Kiichi K Itasaka Satoshi S Yoshimura Michio M Tanimoto Keiji K Torii Masae M Sowa Terumasa T Menju Toshi T Sonobe Makoto M Kakeya Hideaki H Toi Masakazu M Date Hiroshi H Hammond Ester M EM Hiraoka Masahiro M Harada Hiroshi H

Nature communications 20150123

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 pulmona ...[more]

PMID: 25615526

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Project description:BackgroundNeuroblastoma (NB) is the most common pediatric solid tumor that originates from neural crest-derived sympathoadrenal precursor cells that are committed to development of sympathetic nervous system. The well differentiated histological phenotype of NB tumor cells has been reportedly associated with favorable patient outcome. Retinoic acid (RA) can effectively induce NB cell differentiation, thereby being used in the clinic as a treatment agent for inducing the differentiation of high-risk NB. However, the underlying molecular mechanisms of regulating differentiation remain elusive.MethodsThe correlation between clinical characteristics, survival and the deubiquitinating enzyme ubiquitin C-terminal hydrolase 1 (UCHL1) expression were assessed using a neuroblastic tumor tissue microarray, and then validated in three independent patient datasets. The different expression of UCHL1 in ganglioneuroblastoma, ganglioneuroma and NB was detected by immunohistochemistry, mass spectra and immunoblotting analysis, and the correlation between UCHL1 expression and the differentiated histology was analyzed, which was also validated in three independent patient datasets. Furthermore, the roles of UCHL1 in NB cell differentiation and proliferation and the underlying mechanisms were studied by using short hairpin RNA and its inhibitor LDN57444 in vitro.ResultsBased on our neuroblastic tumor tissue microarrays and three independent validation datasets (Oberthuer, Versteeg and Seeger), we identified that UCHL1 served as a prognostic marker for better clinical outcome in NB. We further demonstrated that high UCHL1 expression was associated with NB differentiation, indicated by higher UCHL1 expression in ganglioneuroblastomas/ganglioneuromas and well-differentiated NB than poorly differentiated NB, and the positive correlation between UCHL1 and differentiation markers. As expected, inhibiting UCHL1 by knockdown or LDN57444 could significantly inhibit RA-induced neural differentiation of NB tumor cells, characterized by decreased neurite outgrowth and neural differentiation markers. This effect of UCHL1 was associated with positively regulating RA-induced AKT and ERK1/2 signaling activation. What's more, knockdown of UCHL1 conferred resistance to RA-induced growth arrest.ConclusionOur findings identify a pivotal role of UCHL1 in NB cell differentiation and as a prognostic marker for survival in patients with NB, potentially providing a novel therapeutic target for NB.

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

Publications

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

Similar Datasets

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