title: 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: Key Laboratory of Marine Drugs, Chinese Ministry of Education; Key Laboratory of Glycoscience & Glycotechnology of Shandong Province; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
authors: Xinling
authors: X
authors: Zhang
authors: Key Laboratory of Marine Drugs, Chinese Ministry of Education; Key Laboratory of Glycoscience & Glycotechnology of Shandong Province; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
authors: Leina
authors: L
authors: Ma
authors: Key Laboratory of Marine Drugs, Chinese Ministry of Education; Key Laboratory of Glycoscience & Glycotechnology of Shandong Province; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
authors: Jieqiong
authors: J
authors: Qi
authors: Key Laboratory of Marine Drugs, Chinese Ministry of Education; Key Laboratory of Glycoscience & Glycotechnology of Shandong Province; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
authors: Hui
authors: H
authors: Shan
authors: Key Laboratory of Marine Drugs, Chinese Ministry of Education; Key Laboratory of Glycoscience & Glycotechnology of Shandong Province; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
authors: Wengong
authors: W
authors: Yu
authors: Key Laboratory of Marine Drugs, Chinese Ministry of Education; Key Laboratory of Glycoscience & Glycotechnology of Shandong Province; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China. guych@126.com.
authors: Yuchao
authors: Y
authors: Gu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D014162:Transfection; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; C494112:ELK1 protein, human; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; D050807:ets-Domain Protein Elk-1; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Cancer; MAPK/ERK; O-GlcNAcylation; OGT; Pathway Analysis