A Hypoxia-inducible transcription factor, HIF-1, has been associated with distant tumor metastases; however, genes that activate HIF-1 and promote metastases remain largely unknown. Here we identified Ubiquitin C-terminal hydrolase-L1 (UCHL1) as an novel activator of HIF-1 and revealed that it directly bound to HIF-1α, the regulatory subunit of HIF-1, abrogated the von Hippel-Lindau-mediated ubiquitination of HIF-1α, upregulated HIF-1 activity, and consequently promoted metastasis in murine models of pulmonary metastasis. Blockade of the UCHL1-HIF-1 axis by silencing UCHL1 or a pharmacological UCHL1 inhibitor, LDN57444, suppressed the formation of metastatic tumors. The expression levels of UCHL1 correlated with those of HIF-1α and were 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.

Citation Format: Hiroshi Harada. UCHL1 promotes distant tumor metastasis through its deubiquitinating effect on HIF-1α. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A201.

©2015 American Association for Cancer Research.
2015