O-GlcNAcylation is increased in prostate cancer tissues and enhances malignancy of prostate cancer cells

Abstract

Abstract. O-GlcNAc is an O-linked β-N-acetylglucosamine moiety attached to the side-chain hydroxyl of a serine or threonine residue in numerous cytoplasmic and nuclear proteins. In this study, we detected the level of O-GlcNAc in prostate, liver and pancreatic cancer tissues, and found that the global O-GlcNAc modification also known as O-GlcNAcylation, is specifically increased in prostate cancer tissues compared to corresponding adjacent tissues. In addition, we found that global O-GlcNAcylation is increased in prostate cancer cells and not in benign prostatic hyperplasia (BPH) epithelial cells. O-GlcNAc enhanced the anchorage-independent growth and the migratory/invasive ability of prostate cancer cells. More importantly, we provide here, for the first time to the best of our knowledge, direct evidence that increased O-GlcNAcylation induces malignant transformation of nontumorigenic (BPH) cells. Furthermore, our study suggested that inhibiting the formation of the E-cadherin/catenin/cytoskeleton complex may underly the O-GlcNAc-induced prostate cancer progression. Overall, these findings indicated that O-GlcNAcylation is increased in prostate, but not in liver and pancreatic cancer tissues, and that O-GlcNAc can enhance the malignancy of prostate cancer cells. IntroductionNumerous nuclear and cytoplasmic proteins have been found modified with O-β-N-acetylglucosamine (O-GlcNAc) at the hydroxyl moiety of serine or threonine residues. This moiety is dynamically added and removed by the O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA) enzymes, respectively (1). UDP-GlcNAc is the donor substrate of OGT, and is biosynthesized through the hexosamine pathway (HBP). The HBP flux is highly dependent on glucose and glutamine, with ~3-5% of total glucose entering this pathway (2). O-GlcNAc is a sensor of intracellular glucose metabolism, since the intracellular level of UDP-GlcNAc is the main regulatory factor for the activity of OGT (3). O-GlcNAcylation is altered in metabolism-associated diseases, such as type II diabetes (4-6), Alzheimer's disease (7) and cancer (8). Therefore, abnormal O-GlcNAcylation may play critical roles in these pathological processes.Aberrant metabolism is a hallmark of cancer. Most cancer cells show increased rates of glucose and glutamine utilization, up to 200-fold higher than those observed in the healthy cells they originate from, and predominantly produce energy through glycolysis followed by lactic acid fermentation (9,10). As a glycolytic pathway, HBP can enhance the level of UDP-GlcNAc, and thus, the activity of OGT, which may lead to an increase in the global O-GlcNAc level (summed over all proteins) in cancer cells. We have previously demonstrated that the global O-GlcNAc level is increased in breast, lung and colon cancer tissues as compared to respective adjacent tissues (11,12). In addition, other research groups have shown that O-GlcNAcylation is increased in breast, prostate and pancreatic cancer cell lines (13-15). However, whether increased O-GlcNAcylation is universal in ...

O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling

“…Similar trends have been observed in a number of cancer types including prostate 40; 41; 42; 43 , colon 44; 45; 46; 47; 48 , bladder 49 , hepatocellular carcinoma 50 , leukemia 51; 52 , lung 44; 53 and pancreatic cancer 54 (Table I). Utilizing the Oncomine database, Lynch et al demonstrated that OGT mRNA expression is elevated in prostate cancer tissue compared to normal adjacent tissue in over 200 patients and increased mRNA was associated with a decreased patient five year survival rate 40 .…”

O‐GlcNAcylation in oral squamous cell carcinoma

“…These results were inconsistent with hyper-O-GlcNAcylation and OGT overexpression in squamous cell carcinoma of the larynx, 20 the esophagus,21 and the skin,22 suggesting distinct tissuespecific PTMs. However, our findings are still similar to no differences in O-GlcNAc immunostaining intensities between liver or pancreatic cancer and their adjacent normal tissues 17. Moreover, O-…”

Regulation and clinical significance of O-GlcNAc transferase in cancer

“…Elevated O-GlcNAcylation and OGT levels are existed in breast cancer cell lines and patient tissues [29,30,95,96], and induce tumorigenesis and metastasis via FoxM1 and E-cadherin respectively [29,30]. O-GlcNAcylation, OGT and hexosamine biosynthetic pathway (HBP, a branch of glucose metabolism, controls the level of intracellul UDP-GlcNAc) related proteins are all up-regulated in prostate cancer tissues [33,97], and the hyper-O-GlcNAcylation causes invasion through inhibiting the formation of the E-cadherin/catenin complex and inducing the expression of MMP-2 and MMP-9 [32,33]; in addition, targeting OGT reduces angiogenic potential and VEGF expression via FoxM1 in prostate cancer [32], and increased O-GlcNAc level associates with the poor prognosis of prostate cancer patients [98]. OGT and O-GlcNAcylation elevations are examined in lung and colon cancer tissues and cell lines, and contribute to the etiology and progression of cancer [34,35].…”

“…Given the myriad functions concerned with O-GlcNAcylation, it is exceedingly reasonable that this posttranslational modification plays a fundamental role in the etiology of tumors [6,14,[26][27][28]. Indeed, O-GlcNAcylation is deregulated in many cancer types, including breast [29,30], pancreatic [31], prostate [32,33], colorectal [34,35], lung [34], liver [36], gastric [37,38], laryngeal [39], bladder [40], endometrial [41], esophageal squamous cell carcinoma [42], and nonsolid cancers such as chronic lymphocytic leukemia [43], and contributes to cancer cell metabolic reprogramming, cell proliferation, survival, angiogenesis, invasion, metastasis and cancer cell epigenetics [14,44].…”