O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy

Abstract

O-GlcNAc is a monosaccharide attached to serine or threonine hydroxyl moieties on numerous nuclear and cytoplasmic proteins; O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Although recent studies have shown that O-GlcNAcylation plays essential roles in breast cancer progression, it is also necessary to know whether O-GlcNAcylation is involved in other types of human cancer. In this study, O-GlcNAcylation levels and the expressions of OGT and OGA in human lung and colon cancer tissues were examined by immunohistochemistry analysis. We found that O-GlcNAcylation as well as OGT expression was significantly elevated in the cancer tissues compared with that in the corresponding adjacent tissues. Additionally, the roles of O-GlcNAcylation in the malignancy of lung and colon cancer were investigated in vitro. The results showed that O-GlcNAcylation markedly enhanced the anchorage-independent growth of lung and colon cancer cells; O-GlcNAcylation could also enhance lung and colon cancer invasion in a context-dependent manner. All together, this study suggests that O-GlcNAcylation might play important roles in lung and colon cancer formation and progression, and may be a valuable target for diagnosis and therapy of cancer.

O-Linked β-N-Acetylglucosaminylation (O-GlcNAcylation) in Primary and Metastatic Colorectal Cancer Clones and Effect of N-Acetyl-β-d-glucosaminidase Silencing on Cell Phenotype and Transcriptome

“…1). These findings are in accordance with previous reports describing enhanced O-GlcNAcylation in breast cancer metastatic lymph nodes compared with their primary tumor tissues and increased levels of O-GlcNAcylation and OGT in lung and colon tumor tissues compared with adjacent tissues (10,11). Increased O-GlcNAcylation and elevated OGT expression were also found in several breast cancer cell lines (7).…”

“…Indeed, enhanced growth of the SW620 clone compared with the SW480 clone in both culture and agar was previously shown (29,30). These data suggest that O-GlcNAcylation enhances anchorage-independent growth, an assumption supported by a previous report showing that colony formation by lung and colon cancer cells was reduced by OGT silencing and increased by OGA inhibition (10). Similarly, OGT silencing in breast cancer cells inhibited tumor growth in vitro and in vivo and decreased cell cycle progression (7).…”

“…colon, breast, lung, and liver), O-GlcNAcylation was found to be enhanced, especially in advanced tumors, and in some cases it was linked to cellular features relevant to metastasis, e.g. invasion and migration (7,10,11,19).…”

“…Overexpression of both OGT and OGA disrupted mitosis (possibly by disrupting cyclin expression), and in the case of OGT, overexpression also increased polyploidy, a characteristic of cancer cells (9). Increased OGlcNAcylation and OGT levels were reported in various types of cancer, including colon, lung, and breast cancers (7,10,11), and were found to correlate with the progression of tumorigenesis (10 -12). O-GlcNAcylation was also found to directly affect key proteins involved in tumorigenesis.…”

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

“…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)(14)(15).…”