MAPK/ERK signaling pathway-induced hyper-O-GlcNAcylation enhances cancer malignancy.

Abstract

Dysregulated MAPK/ERK signaling is implicated in one-third of human tumors and represents an attractive target for the development of anticancer drugs. Similarly, elevated protein O-GlcNAcylation and O-GlcNAc transferase (OGT) are detected in various cancers and serve as attractive novel cancer-specific therapeutic targets. However, the potential connection between them remains unexplored. Here, a positive correlation was found between the activated MAPK/ERK signaling and hyper-O-GlcNAcylation in various cancer types and inhibition of the MAPK/ERK signaling by 10 µM U0126 significantly decreased the expression of OGT and O-GlcNAcylation in H1299, BPH-1 and DU145 cells; then, the pathway analysis of the potential regulators of OGT obtained from the UCSC Genome Browser was done, and ten downstream targets of ERK pathway were uncovered; the following results showed that ELK1, one of the ten targets of ERK pathway, mediated ERK signaling-induced OGT upregulation; finally, the MTT assay and the soft agar assay showed that the inhibition of MAPK/ERK signaling reduced the promotion effect of hyper-O-GlcNAcylation on cancer cell proliferation and anchorage-independent growth. Taken together, our data originally provided evidence for the regulatory mechanism of hyper-O-GlcNAcylation in tumors, which will be helpful for the development of anticancer drugs targeting to hyper-O-GlcNAcylation. This study also provided a new mechanism by which MAPK/ERK signaling-enhanced cancer malignancy. Altogether, the recently discovered oncogenic factor O-GlcNAc was linked to the classical MAPK/ERK signaling which is essential for the maintenance of malignant phenotype of cancers.

• Authors: Xinling Zhang, Leina Ma, Jieqiong Qi, Hui Shan, Wengong Yu, Yuchao Gu
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 410 Issue 1-2 Pg. 101-10 (Dec 2015) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 26318312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Butadienes
• ELK1 protein, human
• Nitriles
• Protein Kinase Inhibitors
• U 0126
• ets-Domain Protein Elk-1
• N-Acetylglucosaminyltransferases
• O-GlcNAc transferase
• Extracellular Signal-Regulated MAP Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Butadienes (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Glycosylation
• Humans
• MAP Kinase Signaling System (drug effects)
• N-Acetylglucosaminyltransferases (genetics, metabolism)
• Neoplasms (drug therapy, enzymology, genetics, pathology)
• Nitriles (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Processing, Post-Translational (drug effects)
• RNA Interference
• Transfection
• ets-Domain Protein Elk-1 (genetics, metabolism)