2. Academic Validation
  3. High glucose stimulates proliferative capacity of liver cancer cells possibly via O-GlcNAcylation-dependent transcriptional regulation of GJC1

High glucose stimulates proliferative capacity of liver cancer cells possibly via O-GlcNAcylation-dependent transcriptional regulation of GJC1

  • J Cell Physiol. 2018 Jan;234(1):606-618. doi: 10.1002/jcp.26803.
Yan Chen 1,  Rui Liu 2,  Zhexuan Chu 3,  Bu Le 4,  Hong Zeng 5,  Xiao Zhang 1,  Qi Wu 1,  Guoqing Zhu 1,  Yuxin Chen 1,  Ya Liu 1,  Fenyong Sun 1,  Zhicheng Lu 6,  Yongxia Qiao 7,  Jiayi Wang 1 8
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Department of Scientific Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 3 College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
  • 4 Department of Endocrinology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 5 Department of Pathology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China.
  • 6 Department of Medical Affairs Office, Shanghai seventh People's Hospital, Shanghai, China.
  • 7 School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 8 Advanced Institute of Translational Medicine, Tongji University, Shanghai, China.
PMID: 30078215 DOI: 10.1002/jcp.26803
Abstract

Although it is generally accepted that diabetes is one of the most important risk factors for liver Cancer, the underlying mechanism is still not well understood. The purpose of the current study is to further investigate how high concentrations of glucose (HG), a major symptom of diabetes, stimulate the development of liver malignancy. Using data mining, Gap Junction Protein gamma 1 (GJC1) was identified as a critical proto-oncoprotein that is essential for the HG stimulation of proliferative capacity in liver Cancer cells. Furthermore, enhanced transcriptional expression of GJC1 might occur after stimulation by HG. A transcription factor zinc finger protein 410 (APA1)-binding motif was found to be located at the -82 to -77 nt region within the GJC1 promoter. Without APA1, HG was unable to increase GJC1 expression. Interestingly, APA1, but not GJC1, can be O-GlcNAcylated in liver Cancer cells. Moreover, O-GlcNAcylation is essential for HG-induced APA1 binding to the GJC1 promoter. Notably, global O-GlcNAcylation and expression of APA1 and GJC1 were highly elevated in liver Cancer patients with diabetes compared to those in patients without diabetes. The HG-stimulated proliferative capacity was abolished upon decreasing O-GlcNAcylation, which could be reversed gradually by the simultaneous overexpression of APA1 and GJC1. Therefore, GJC1 could be a potential target for preventing liver Cancer in patients with diabetes.

Keywords

APA1; diabetes; liver cancer; promoter; transformative phenotypes.

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