title: Reciprocal regulation between O-GlcNAcylation and tribbles pseudokinase 2 (TRIB2) maintains transformative phenotypes in liver cancer cells.
abstract: TRIB2 has been identified as an onco-protein, and O-GlcNAcylation of target proteins has been reported to stimulate transformative phenotypes in liver cancer cells. However, the relationships between TRIB2 and O-GlcNAcylation are still unknown. The aim of this study was to investigate whether and how O-GlcNAcylation and TRIB2 regulate each other. We found that stimulation of O-GlcNAcylation elevates TRIB2 by enhancing its protein stability. TRIB2 can be O-GlcNAcylated by the hexosamine biosynthesis pathway (HBP). Also, O-GlcNAcylation boosting of transformative phenotypes of liver cancer cells might occur in a TRIB2-dependent manner. Interestingly, TRIB2 stimulated the metabolism of HBP, demonstrating that TRIB2 has positive feedback on O-GlcNAcylation. Notably, TRIB2 was found to maintain the stability of guanylate cyclase 1 alpha 3 (GUCY1A3), a key component of HBP, by interacting GUCY1A3 and reducing its ubiquitination. Importantly, TRIB2-dependent regulation of metabolism, transformative phenotypes, and O-GlcNAcylation all rely on GUCY1A3. Mouse experiments demonstrate that O-GlcNAcylation of TRIB2 is much higher in the livers of diabetic mice compared to control mice, suggesting that O-GlcNAcylation of TRIB2 might be critical for diabetes-associated liver cancer. Collectively, we have uncovered a positive auto-regulatory feedback between O-GlcNAcylation and TRIB2, which might be regarded as a promising therapeutic target for liver cancer.
authors: Department of Clinical Laboratory, the First Hospital affiliated to Dalian Medical University, Dalian, Liaoning Province 116011, China.
authors: Bingjie
authors: B
authors: Yao
authors: Department of Pharmacy, Dongjing Town Community Health Service Center, Songjiang District, Shanghai 201619, China.
authors: Yanli
authors: Y
authors: Xu
authors: Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China; Tongji University Advanced Institute of Translational Medicine, Shanghai 200092, China. Electronic address: karajan2@163.com.
authors: Jiayi
authors: J
authors: Wang
authors: School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors: Yongxia
authors: Y
authors: Qiao
authors: Department of Laboratory Centre, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors: Yue
authors: Y
authors: Zhang
authors: Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors: Xiao
authors: X
authors: Zhang
authors: Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors: Yan
authors: Y
authors: Chen
authors: Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors: Qi
authors: Q
authors: Wu
authors: Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors: Yinghui
authors: Y
authors: Zhao
authors: Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors: Guoqing
authors: G
authors: Zhu
authors: Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors: Fenyong
authors: F
authors: Sun
authors: Department of Clinical Laboratory, Shanghai Yangpu Hospital of Tongji University, Shanghai 200090, China. Electronic address: lizhsh2001@163.com.
authors: Zhi
authors: Z
authors: Li
authors: Department of Clinical Laboratory, the First Hospital affiliated to Dalian Medical University, Dalian, Liaoning Province 116011, China. Electronic address: yuanhonglab@163.com.
authors: Hong
authors: H
authors: Yuan
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005947:Glucose / Q000494:pharmacology; D006031:Glycosylation / Q000187:drug effects; D006595:Hexosamines / Q000096:biosynthesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008819:Mice, Nude; D008954:Models, Biological; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism
chemical_list: C000605661:GUCY1A1 protein, human; D006595:Hexosamines; D047908:Intracellular Signaling Peptides and Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human; D000071756:Soluble Guanylyl Cyclase; D005947:Glucose; D000117:Acetylglucosamine
keywords: Diabetes; GUCY1A3; Hexosamine biosynthesis pathway (HBP); High glucose; Protein stability