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J Biol Chem. 2018 Sep 7;293(36):13989-14000. doi: 10.1074/jbc.RA118.004709. Epub 2018 Jul 23.

Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer.

Qian K1,2,3, Wang S1,2,4, Fu M1,2, Zhou J4, Singh JP1,2, Li MD1,2,3, Yang Y1,2, Zhang K1,2,3, Wu J1,2,5, Nie Y4, Ruan HB6, Yang X7,2,3.

Author information

1
From the Program in Integrative Cell Signaling and Neurobiology of Metabolism and.
2
the Departments of Comparative Medicine and.
3
Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510.
4
the State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
5
the School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China, and.
6
the Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota 55455.
7
From the Program in Integrative Cell Signaling and Neurobiology of Metabolism and xiaoyong.yang@yale.edu.

Abstract

Many intracellular proteins are reversibly modified by O-linked GlcNAc (O-GlcNAc), a post-translational modification that dynamically regulates fundamental cellular processes in response to diverse environmental cues. Accumulating evidence indicates that both excess and deficiency of protein O-GlcNAcylation can have deleterious effects on the cell, suggesting that maintenance of O-GlcNAc homeostasis is essential for proper cellular function. However, the mechanisms through which O-GlcNAc homeostasis is maintained in the physiologic state and altered in the disease state have not yet been investigated. Here, we demonstrate the existence of a homeostatic mechanism involving mutual regulation of the O-GlcNAc-cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) at the transcriptional level. Specifically, we found that OGA promotes Ogt transcription through cooperation with the histone acetyltransferase p300 and transcription factor CCAAT/enhancer-binding protein β (C/EBPβ). To examine the role of mutual regulation of OGT and OGA in the disease state, we analyzed gene expression data from human cancer data sets, which revealed that OGT and OGA expression levels are highly correlated in numerous human cancers, particularly in pancreatic adenocarcinoma. Using a KrasG12D -driven primary mouse pancreatic ductal adenocarcinoma (PDAC) cell line, we found that inhibition of extracellular signal-regulated kinase (ERK) signaling decreases OGA glycosidase activity and reduces OGT mRNA and protein levels, suggesting that ERK signaling may alter O-GlcNAc homeostasis in PDAC by modulating OGA-mediated Ogt transcription. Our study elucidates a transcriptional mechanism that regulates cellular O-GlcNAc homeostasis, which may lay a foundation for exploring O-GlcNAc signaling as a therapeutic target for human disease.

KEYWORDS:

CCAAT-enhancer-binding protein (C/EBP); E1A binding protein p300 (P300); O-GlcNAcase (OGA); O-GlcNAcylation; O-linked N-acetylglucosamine (O-GlcNAc); O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT); extracellular-signal-regulated kinase (ERK); pancreatic cancer

PMID:
30037904
PMCID:
PMC6130940
[Available on 2019-09-07]
DOI:
10.1074/jbc.RA118.004709
[Indexed for MEDLINE]

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