Zhang Xinling, Ma Leina, Qi Jieqiong, Shan Hui, Yu Wengong, Gu Yuchao
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.
Mol Cell Biochem. 2015 Dec;410(1-2):101-10. doi: 10.1007/s11010-015-2542-8. Epub 2015 Aug 29.
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.
失调的丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）信号传导与三分之一的人类肿瘤有关，是抗癌药物开发的一个有吸引力的靶点。同样，在各种癌症中都检测到蛋白质O-连接的N-乙酰葡糖胺（O-GlcNAc）糖基化水平升高和O-GlcNAc转移酶（OGT）增加，它们是有吸引力的新型癌症特异性治疗靶点。然而，它们之间的潜在联系仍未被探索。在这里，研究发现各种癌症类型中活化的MAPK/ERK信号传导与高O-GlcNAc糖基化之间存在正相关，10μM U0126抑制MAPK/ERK信号传导显著降低了H1299、BPH-1和DU145细胞中OGT的表达和O-GlcNAc糖基化；然后，对从加州大学圣克鲁兹分校基因组浏览器获得的OGT潜在调节因子进行了通路分析，发现了ERK通路的10个下游靶点；接下来的结果表明，ERK通路的10个靶点之一ELK1介导了ERK信号诱导的OGT上调；最后，MTT法和软琼脂法表明，抑制MAPK/ERK信号传导降低了高O-GlcNAc糖基化对癌细胞增殖和非锚定依赖性生长的促进作用。综上所述，我们的数据首次为肿瘤中高O-GlcNAc糖基化的调控机制提供了证据，这将有助于开发针对高O-GlcNAc糖基化的抗癌药物。本研究还提供了一种新的机制，即MAPK/ERK信号传导增强癌症恶性程度。总之，最近发现的致癌因子O-GlcNAc与经典的MAPK/ERK信号传导相关，而MAPK/ERK信号传导对于维持癌症的恶性表型至关重要。
