The USP18-FBXO6 axis maintains the malignancy of ovarian cancer.

ABSTRACT

Ubiquitin-specific protease 18 (USP18) is a deubiquitinating enzyme that reverses the post-translational modification of target proteins by ISG15 or ubiquitin, and is involved in a variety of cellular processes, including signal transduction, viral infection, and cancer development. Although high levels of USP18 mRNA have been observed in several types of cancer, its pathological significance in ovarian cancer (OV) is still elusive. Here, by integrating the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Genotypic Tissue Expression (GTEx) databases, we found that USP18 was abnormally up-regulated in OV tissues, and the increased expression of USP18 was associated with poor prognosis. We further showed that activated Jak-STAT3 signaling induced the expression of USP18, which in turn feedback maintained the activity of Jak-STAT3 signaling in OV. In addition, we found that USP18 played a cancer-promoting role in OV mainly through the transcriptional regulation of FBXO6. Silencing USP18 reduced the malignancy of OV, which can be largely reversed by overexpression of FBXO6. On the contrary, silencing FBXO6 significantly weaken the pro-proliferation function of USP18 in OV cells. In summary, our results indicate that USP18 is a downstream target gene of STAT3, and the USP18-FBXO6 axis might be a promising therapeutic target for OV.