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.