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.

The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways

“…During the initial phases of adhesion, UCHL1 accumulates at the motile edge of the cell membrane; co-localizes with FAK, p120-catenin, and vinculin; enhances the formation of focal adhesion; and promotes FAK activation [27]. Recent research has demonstrated that UCHL1 provides diagnostic and antimetastatic strategies due to its de-ubiquitinating effect on HIF-1α [28]. In MKN45 and BGC823 cells, UCHL1 may increase cell motility ability through activation of FAK by Akt or Erk1/2 signaling pathway.…”

Proteomic analysis of β-asarone induced cytotoxicity in human glioblastoma U251 cells

“…UCHL1 also acts as a colorectal cancer oncogene via activation of the beta-catenin/TCF pathway through its deubiquitinating activity [20]. Recently, UCHL1 is reported to promote metastases as a deubiquitinating enzyme for HIF-1␣ [21]. On the other hand, promoter hypermethylation leading to silencing of UCHL1 has been reported in progression of prostate cancer [22], breast cancer [23], nasopharyngeal carcinoma [24], hepatocellular carcinoma and other digestive tumors [25].…”

A Proteomic Analysis of the Malignant Mesothelioma Secretome Using iTRAQ

“…CypA has been shown to stimulate cell motility and invasion by binding to the adaptor protein CrkII and preventing it from switching to its inactive form (38). Another potentially important up-CANCER GENOMICS & PROTEOMICS 14: 103-118 (2017) 112 regulated protein identified in this study is Ubiquitin C-terminal hydrolase-L1 (UCHL1), which promotes metastasis by deubiquitinating hypoxia inducible factor (HIF-1α) (39). The expression levels of UCHL1 in lung and breast cancer patients are a strong negative prognostic factor (39).…”

“…Another potentially important up-CANCER GENOMICS & PROTEOMICS 14: 103-118 (2017) 112 regulated protein identified in this study is Ubiquitin C-terminal hydrolase-L1 (UCHL1), which promotes metastasis by deubiquitinating hypoxia inducible factor (HIF-1α) (39). The expression levels of UCHL1 in lung and breast cancer patients are a strong negative prognostic factor (39). Lectin galactoside-binding soluble 3 binding protein (LGALS3BP) has been previously shown to be elevated in pleural effusions from MM patients (40) and, paradoxically, its effusion level is positively associated with survival (40).…”