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

Kevin Qian, Simeng Wang, Minnie Fu, Jinfeng Zhou, Jay Prakash Singh, Min Dian Li, Yunfan Yang, Kaisi Zhang, Jing Wu, Yongzhan Nie, Hai Bin Ruan, Xiaoyong Yang

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Many intracellular proteins are reversibly modified by Olinked 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 (C/EBP). 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.

Original languageEnglish (US)
Pages (from-to)13989-14000
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number36
DOIs
StatePublished - Sep 7 2018

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