Abstract
O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) increases O-GlcNAc modification (O-GlcNAcylation), and transcriptional co-regulator host cell factor 1 (HCF-1) is one of OGT targets. High-risk Human Papillomaviruses (HPVs) encode E6 and E7 oncoproteins, which promote cervical cancer. Here, we tested whether O-GlcNAc modification of HCF-1 affects HPV E6 and E7 expressions and tumorigenesis of cervical cancer. We found that depleting OGT with OGT-specific shRNA significantly decreased levels of E6 and E7 oncoproteins, and cervical cancer tumorigenesis, while OGT overexpression greatly increased levels of E6 and E7 oncoproteins. Notably, OGT overexpression caused dose-dependent increases in the transcriptional activity of E6 and E7, and this activity was decreased when HCF-1 was depleted with HCF-1-specific siRNA. Moreover, OGT depletion reduced proliferation, invasion, and metastasis in cervical cancer cells. Further, high glucose enhanced the interaction between OGT and HCF-1, paralleling increased levels of E6 and E7 in cervical cancer cells. Most importantly, we found that reducing OGT in HeLa cells caused decreased tumor growth in vivo. These findings identify OGT as a novel cellular factor involved in E6 and E7 expressions and cervical cancer tumorigenesis, suggesting that targeting OGT in cervical cancer may have potential therapeutic benefit.
Highlights
Cervical cancer is one of the leading cause of cancerrelated deaths worldwide among young women and caused by a persistent infection with human papillomaviruses (HPVs) [1], and current treatment options are insufficient.O-linked N-acetylglucosaminylation (O-GlcNAcyl ation) is a reversible posttranslational modification of serine/threonine residues [2,3,4]
Because the OGT and O-GlcNAcylation levels are elevated in various cancers, and OGT partners with transcriptional regulator such as host cell factor 1 (HCF-1), and proteolytic processing of HCF-1 is required for activating the function of HCF-1 [15, 16, 18], we examined the O-GlcNAcylation and HCF-1 levels in cervical cancer tissues by western blot and immunohistochemistry analysis
Immunohistochemical analysis showed that levels of O-GlcNAc, OGT, HCF1, and HPV16/18 E6 were significantly increased, in the intermediate layer of cervical cancer tissues compared to normal cervical tissues, paralleling staining of Ki-67 (Figure 1E), a DNA proliferation marker increased in cervical intra-epithelial neoplasia (CIN) [20]
Summary
Cervical cancer is one of the leading cause of cancerrelated deaths worldwide among young women and caused by a persistent infection with human papillomaviruses (HPVs) [1], and current treatment options are insufficient. O-linked N-acetylglucosaminylation (O-GlcNAcyl ation) is a reversible posttranslational modification of serine/threonine residues [2,3,4]. O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) mediates O-GlcNAcylation of various proteins implicated in various disorders, and couples nutrient excess, an important risk factor, to protein activities and cellular function. Increased O-GlcNAcylation is a hallmark in various cancers [5,6,7]. The increased glucose flux through hexosamine biosynthetic pathway (HBP) results in accumulation of UDP-O-linked N-acetyl-glucosamine (UDP-O-GlcNAc), which is the donor sugar nucleotide used by OGT in the process of O-GlcNAcylation. OGT is required for tumor growth and colony formation in vitro [8], and invasion and metastasis in vivo [9, 10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
