UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α.
Goto Y., Zeng L., Yeom CJ., Zhu Y., Morinibu A., Shinomiya K., Kobayashi M., Hirota K., Itasaka S., Yoshimura M., Tanimoto K., Torii M., Sowa T., Menju T., Sonobe M., Kakeya H., Toi M., Date H., Hammond EM., Hiraoka M., Harada H.
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.