O-GlcNAcylation plays a role in tumor recurrence of hepatocellular carcinoma following liver transplantation

Abstract

O-linked-ß-N-acetylglucosamine (O-GlcNAc) modification is a crucial post-translational modification. The enzymes responsible for the addition and removal of O-GlcNAc have been identified as O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In this study, O-GlcNAcylation level was examined in forty hepatocellular carcinoma (HCC) tissues of patients who underwent liver transplantation (LT) and ten healthy liver tissues by immunohistochemistry analysis. We also examined the expression of OGT and OGA in sixty HCC samples using real-time reverse-transcription polymerase chain reaction and analyzed their correlations with clinical parameters and prognosis in sixty HCC patients treated with LT. Additionally, the global O-GlcNAcylation level was altered through OGT and OGA silencing in the HCC cell line, and the effects of O-GlcNAcylation on cancer malignancy were investigated. We found that the global O-GlcNAcylation levels were significantly elevated in HCC tissues than that in healthy liver tissues (P = 0.031); moreover, O-GlcNAcylation was significantly enhanced in the tumor tissues of patients who had suffered from HCC recurrence after LT compared with those who had not (P = 0.046). Importantly, low expression of OGA was an independent prognostic factor for predicting tumor recurrence of HCC following LT (P = 0.041, hazard ratio, 0.438), especially in AFP low patients. In vitro assays demonstrated that O-GlcNAcylation play important roles in migration, invasion, and viability of HCC cells, partly through regulating E-cadherin, MMP1, MMP2, and MMP3 expression. Altogether, these results suggest that O-GlcNAcylation might play important roles in HCC formation and progression and may be a potential marker to predict patient risk of recurrence after LT and a valuable target for therapy.

Triptolide-induced Cell Death in Pancreatic Cancer Is Mediated by O-GlcNAc Modification of Transcription Factor Sp1

“…Increased activation of the HBP in turn results in increased glycosylation by O-GlcNAc transferase (OGT), an enzyme that modifies many key cellular proteins and transcription factors (6). OGT is reported to be necessary for cell survival (7) and is overexpressed in a number of cancers (8 -10). This pathway is thus an early cellular protective response to stress because this protein modification can occur rapidly (5).…”

Critical Role of O-Linked β-N-Acetylglucosamine Transferase in Prostate Cancer Invasion, Angiogenesis, and Metastasis

“…Increasing evidence suggests that OGT plays a critical role during oncogenesis and tumor progression in numerous cancers; indeed, several reports have implicated OGT overexpression and elevated O-GlcNAcylation in cancers ranging from solid tumors (including breast (16,18), lung (23), colon (23), liver (36), and now prostate)) to chronic myeloid leukemia (16,17,23,24). More recently, expression of the enzyme that removes O-GlcNAcylation, O-GlcNAcase, has been found to be reduced in breast (37) and liver (36) cancer.…”

“…More recently, expression of the enzyme that removes O-GlcNAcylation, O-GlcNAcase, has been found to be reduced in breast (37) and liver (36) cancer. Knockdown of O-GlcNAcase in liver cancer cells increases total OGlcNAcylation levels and increases the migration and invasion of these cells.…”

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

“…Reducing hyper-O-GlcNAcylation in prostate cancer PC-3ML and liver cancer HepG2 cells suppresses the expression of MMP-2 and MMP-9 (9, 12). Conversely, elevation of O-GlcNAcylation using the OGA inhibitor Thiamet-G or knockdown of OGA enhances the activity of MMP-2 and MMP-9 in chondrocytes and increases the expression of MMP-1, MMP-2, and MMP-3 (12,76). Therefore, hyper-O-GlcNAcylation in tumors may contribute to angiogenesis through up-regulation of VEGF and MMPs.…”