title: Modification of p27 with O-linked N-acetylglucosamine regulates cell proliferation in hepatocellular carcinoma.
abstract: The tumor suppressor p27, which is a member of the Cip/Kip family of Cyclin-dependent kinase inhibitory proteins (CKIs), controls anti-proliferative events. The post-translational addition of O-GlcNAc to p27 occurs in HEK293T and HCC (hepatocellular carcinoma) cell lines, and we identified Ser2, Ser106, Ser110, Thr157, and Thr198 as the glycosylation sites of p27 based on the Q-TOF spectrum. Here, immunoprecipitation analysis showed that Ser2 was O-GlcNAcylated and that this modification was associated with the increased phosphorylation of p27 at Ser10, ultimately resulting in p27 accumulation in the cytoplasm and increased p27 ubiquitination. In addition, O-GlcNAcylation at Ser2 suppressed Cyclin/CDK complex-p27 interactions by promoting the nuclear export of p27, thus facilitating cell cycle progression. Cell proliferation was negatively regulated when Ser2 of p27 was replaced with Ala. Furthermore, western blot and immunohistochemical analyses of HCC tissues and their corresponding nontumorous tissues were performed, and we found that O-GlcNAcylated p27 correlated with cell proliferation in HCC. Together, our results indicate that the dynamic interplay between O-GlcNAcylation and p27 phosphorylation coordinates and regulates cell proliferation in hepatocellular carcinoma. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, PR China.|Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Guizhou
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, PR China.|Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Runzhou
authors.initials: R
authors.lastname: Ni
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, PR China.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D054875:Ubiquitination
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D000117:Acetylglucosamine
keywords: HCC; O-GlcNAcylation; p27kip1; phosphorylation; tumor promotion