USP4 expression independently predicts favorable survival in lung adenocarcinoma.

Ubiquitin specific protease 4 (USP4) is a member of the USPs family, which catalyzes the cleavage of ubiquitin from a series of protein substrates, thereby modulating a number of cellular signaling pathways. In this study, we aimed to explore the expression profile of USP4 in lung adenocarcinoma (LUAD) using large patient cohorts in the Cancer Genome Atlas and the International Cancer Genome Consortium and to investigate its prognostic value and the possible mechanisms of its dysregulation. Results showed that USP4 was significantly downregulated in LUAD tissues (N = 514) compared with the normal controls (N = 59). The high USP4 expression group had significantly better overall survival (OS) and recurrence-free survival (RFS). Multivariate analysis showed that preserved USP4 expression was an independent prognostic factor of favorable OS (HR: 0.574, 95%CI: 0.427-0.771, P < 0.001) and RFS (HR: 0.625, 95%CI: 0.444-0.880, P = 0.007) in LUAD. In comparison, although USP4 was downregulated in lung squamous cell carcinoma, its expression had no prognostic value in term of OS and RFS. By examining USP4 DNA copy number alterations (CNAs) (N = 511) and DNA methylation (N = 453) in LUAD, we found that DNA shallow deletion was frequent (-1, N = 239, 46.8%) and was associated with significantly decreased USP4 expression compared with the copy-neutral (0) cases. The methylation status of some CpG sites in USP4 DNA was negatively correlated with USP4 expression. Based on these findings, we infer that USP4 expression might be a favorable biomarker in terms of OS and RFS in LUAD patients. DNA shallow deletion and hypermethylation might be two important mechanisms of decreased USP4 in these patients. © 2018 IUBMB Life, 70(7):670-677, 2018.