The development of head and neck squamous cell carcinoma (HNSCC) is a complex pathological process and many cellular and molecular events may occur. The ubiquitin conjugating enzyme E2 (UBE2C) was found to play an oncogenic role in several human cancers. However, its functional role in HNSCC tumorigenesis remains unknown. In this study, UBE2C gene expression in HNSCC was first evaluated using the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The connection between UBE2C gene expression and patients' survival rates of HNSCC and other human cancers was also investigated. Liquid chromatography with tandem mass spectrometry was used to identify differentially expressed proteins, including UBE2C, between UMSCC1 oral cancer cells and normal human oral keratinocytes (NHOKs). Immunohistochemistry (IHC) was used to verify the differential expression of UBE2C protein between HNSCC and adjacent control tissues. Cell cycle analysis, MIT, colony formation, Transwell migration, and Matrigel invasion assays were used to study the effect of UBE2C downregulation on the malignant phenotypes of HNSCC cells. The bioinformatic analysis of the proteins interacting with UBE2C in HNSCC cells was also performed. Based on the data obtained from the cancer databases and our in vitro studies, we found that UBE2C was overexpressed in HNSCC and patients with high UBE2C expression suffered a remarkably worse overall survival rate than those with low UBE2C expression, and a similar observation was found in a number of other human cancers. UBE2C was also found to be overexpressed in HNSCC cells versus normal human oral keratinocytes and inhibition of UBE2C expression significantly suppressed the malignant phenotypes of HNSCC cells in vitro. The bioinformatic analysis indicated that UBE2C may be involved in head and neck tumorigenesis through the mediation of important pathways such as ubiquitin mediated proteolysis, proteasome, and cell cycle. In conclusion, our results suggest that UBE2C is consistently upregulated in many human solid tumors. It promotes HNSCC progression and may serve as a potential prognostic biomarker in HNSCC. Future studies are warranted to unveil the underlying molecular pathways of UBE2C in HNSCC. (C) 2019 Elsevier Inc. All rights reserved.