O-GlcNAcylation modulates Bmi-1 protein stability and potential oncogenic function in prostate cancer

Wang, L; Liu, Jing; Zhang, P; An, Ming; Han, Chuanchun; Li, Y; Guan, Xin; Zhang, K

doi:10.1038/onc.2017.223

Cited by 44 publications

(37 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Polycomb group (PcG) proteins are epigenetic gene-silencing proteins that have been shown to play important roles in human cancer occurrence and progression [27,28]. Bmi-1, the first functionally identified PcG member, is frequently dysregulated in various cancers and strongly correlates with tumor aggressiveness; thus, its presence predicts a poor prognosis [10,29,30], but little attention has been paid to the downstream regulatory mechanism of Bmi-1 in GC promotion. The opposite biological functions and negative correlation between Bmi-1 and RKIP suggested a potential regulatory mechanism in GC.…”

Section: Discussionmentioning

confidence: 99%

Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer

Tian

Tan

et al. 2020

Mol Cancer

View full text Add to dashboard Cite

Background: We previously reported an inverse relationship between B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP), which is associated with the prognosis of gastric cancer (GC). In this study, we further explored the microRNA (miRNA) regulatory mechanism between Bmi-1 and RKIP. Methods: Microarray analysis was first carried out to identify miRNA profiles that were differentially expressed in cells overexpressing Bmi-1. Then, miRNAs that could regulate RKIP were identified. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of Bmi-1, miR-155, miR-27a and RKIP. RKIP was confirmed as a target of miR-27a and miR-155 through luciferase reporter assays, qRT-PCR and Western blotting. The effects of the Bmi-1/miR-27a/RKIP and Bmi-1/miR-155/RKIP axes on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo. Results: The downregulation of RKIP by Bmi-1 occurred at the protein but not mRNA level. This indicates probable posttranscriptional regulation. miRNA expression profiles of cells with ectopic expression of Bmi-1 were analyzed and compared to those of control cells by microarray analysis. A total of 51 upregulated and 72 downregulated miRNAs were identified. Based on publicly available algorithms, miR-27a and miR-155 were predicted, selected and demonstrated to target RKIP. Bmi-1, miR-27a and miR-155 are elevated in human GC and associated with poor prognosis of GC, while RKIP is expressed at lower levels in GC and correlated with good prognosis. Then, in vitro tests shown that in addition to regulating RKIP expression via miR-27a and miR-155, Bmi-1 was also able to regulate the migration, invasion, proliferation, colony-formation ability and chemosensitivity of GC cells through the same pathway. Finally, the in vivo test showed similar results, whereby the knockdown of the Bmi-1 gene led to the inhibition of tumor growth, metastasis and chemoresistance through miR-27a and miR-155.

show abstract

Section: Discussionmentioning

confidence: 99%

Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer

Tian

Tan

et al. 2020

Mol Cancer

View full text Add to dashboard Cite

show abstract

“…60 O-GlcNAcylation of particular proteasome substrates has long been known to inhibit their degradation. 61–65 Surprisingly, however, we discovered through a variety of chemical biology, biochemical, and cellular approaches that O-GlcNAcylation is required for the optimal activity of the ubiquitin E3 ligase complex that targets NRF2 for destruction under unstressed conditions. 60 We showed that OGT directly modifies Ser104 of KEAP1, the adaptor protein in this complex, and that Ser104-O-GlcNAc is required for both optimal binding of KEAP1 to E3 ligase CUL3 and for NRF2 ubiquitination by the KEAP1–CUL3 complex.…”

Section: Protein–protein Interactions Induced By O-glcnacmentioning

confidence: 99%

A Sweet Embrace: Control of Protein–Protein Interactions by O-Linked β-N-Acetylglucosamine

2017

View full text Add to dashboard Cite

O-Linked β-N-acetylglucosamine (O-GlcNAc) is a critical post-translational modification (PTM) of thousands of intracellular proteins. Reversible O-GlcNAcylation governs many aspects of cell physiology and is dysregulated in numerous human diseases. Despite this broad pathophysiological significance, major aspects of O-GlcNAc signaling remain poorly understood, including the biochemical mechanisms through which O-GlcNAc transduces information. Recent work from many laboratories, including our own, has revealed that O-GlcNAc, like other intracellular PTMs, can control its substrates’ functions by inhibiting or inducing protein–protein interactions. This dynamic regulation of multiprotein complexes exerts diverse downstream signaling effects in a range of processes, cell types, and organisms. Here, we review the literature about O-GlcNAc-regulated protein–protein interactions and suggest important questions for future studies in the field.

show abstract

“…In many OGT substrates, residues modified by O-GlcNAcylation are also subject to phosphorylation by Ser/Thr kinases, providing a link between metabolism and diverse types of cell signaling (22)(23)(24). OGT has been implicated in coupling epigenetic regulation to cell metabolism via altered histone modifications (25)(26)(27), regulation of Polycomb group proteins and other chromatin modifiers (21,28,29), and by its binding to and modification of TET DNA demethylases (19,26,30,31).…”

Section: Introductionmentioning

confidence: 99%

O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors

Efimova

Appelbe

Ricco

et al. 2019

Molecular Cancer Research

View full text Add to dashboard Cite

The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein posttranslational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double-strand break (DSB) repair and resistance to therapyinduced senescence in cancer cells. We have examined the effects of modulating O-GlcNAcylation on the DNA damage response (DDR) in MCF7 human mammary carcinoma in vitro and in xenograft tumors. Proteomic profiling revealed deregulated DDR pathways in cells with altered O-GlcNAcylation. Promoting protein O-GlcNAc modification by targeting O-GlcNAcase or simply treating animals with GlcNAc protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by blocking O-GlcNAc transferase activity led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DDR, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy. Implications: The finding that the HBP, via its impact on protein O-GlcNAcylation, is a key determinant of the DDR in cancer provides a mechanistic link between metabolic reprogramming, genomic instability, and therapeutic response and suggests novel therapeutic approaches for tumor radiosensitization.

show abstract

O-GlcNAcylation modulates Bmi-1 protein stability and potential oncogenic function in prostate cancer

Cited by 44 publications

References 37 publications

Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer

Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer

A Sweet Embrace: Control of Protein–Protein Interactions by O-Linked β-N-Acetylglucosamine

O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors

Contact Info

Product

Resources

About