<i>O</i>-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1

Sekine, Hiroshi; Okazaki, Kazuyuki; Kato, Koichiro; Alam, Md. Morshedul; Shima, Hiroki; Katsuoka, Fumiki; Tsujita, Teppei; Suzuki, Norio; Kobayashi, Akira; Igarashi, Kazuhiko; Yamamoto, Masayuki; Motohashi, Hozumi

doi:10.1128/mcb.00252-18

Cited by 52 publications

(71 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It seems possible that the Nrf2-sMaf heterodimer forms stable complexes only when it interacts with particular neighboring transcription factors or when it interacts with the promoter complexes through appropriate transcriptional cofactors. Since it has been reported that Nrf1 and Nrf2 recruit different transcriptional cofactors to exert their transactivation activities (49)(50)(51), these cofactors may also confer target gene specificity to these CNC factors.…”

Section: Discussionmentioning

confidence: 99%

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Katsuoka

Otsuki

Takahashi

et al. 2019

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

A group of cytoprotective genes is regulated by heterodimers composed of the cap’n’collar (CNC) family member Nrf2 and one of the small Maf (sMaf) proteins (MafF, MafG, or MafK) through the antioxidant response element (ARE, also referred to as the CNC-sMaf binding element [CsMBE]). Many lines of evidence support this model; however, a direct and specific evaluation of the Nrf2-sMaf heterodimer remains to be executed. To address this issue, we constructed a tethered Nrf2-MafG (T-N2G) heterodimer using a flexible linker peptide. We then introduced the T-N2G construct into cells lacking all three sMaf proteins to specifically evaluate the function of the tethered heterodimer without interference from other endogenous CNC-sMaf heterodimers or sMaf homodimers. In response to an Nrf2 activator, diethyl maleate, the T-N2G protein can widely activate the target genes of Nrf2 but not those of Nrf1, such as proteasome subunit genes. Genome-wide binding analysis showed that the T-N2G protein preferentially bound to the CsMBE motifs in the regulatory regions of the Nrf2 target genes. These results provide direct evidence that the Nrf2-MafG heterodimer acts as a transcriptional activator of Nrf2-dependent genes and show that this assay system will be a powerful tool to specifically examine the function of other CNC-sMaf heterodimers.

show abstract

Section: Discussionmentioning

confidence: 99%

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Katsuoka

Otsuki

Takahashi

et al. 2019

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In breast cancer cells, Nrf1 can be stabilized by OGT through O-GlcNAcylation at Ser448 and Ser451, a modification that suppresses the ubiquitinproteasome mediated degradation of Nrf1. In contrast, reduced expression of Nrf1 suppresses its invasion and migration ability (115,128). In summary, crosstalk between O-GlcNAcylation and other PTMs plays critical roles in regulating cancer metastasis.…”

Section: Interplay Between O-glcnacylation and Other Ptms In Cancer Mmentioning

confidence: 99%

Functional Analysis of O-GlcNAcylation in Cancer Metastasis

Jin

Qiu

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

One common and reversible type of post-translational modification (PTM) is the addition of O-linked b-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), and its dynamic balance is controlled by O-GlcNAc transferase (OGT) and glycoside hydrolase O-GlcNAcase (OGA) through the addition or removal of O-GlcNAc groups. A large amount of research data confirms that proteins regulated by O-GlcNAcylation play a pivotal role in cells. In particularly, imbalanced levels of OGT and O-GlcNAcylation have been found in various types of cancers. Recently, increasing evidence shows that imbalanced O-GlcNAcylation directly or indirectly impacts the process of cancer metastasis. This review summarizes the current understanding of the influence of O-GlcNAc-proteins on the regulation of cancer metastasis. It will provide a theoretical basis to further elucidate of the molecular mechanisms underlying cancer emergence and progression.

show abstract

“…Thus, Nrf1 is critically implicated in a variety of important physio-pathological processes by governing expression of crucial genes in order to reinforce antioxidant, detoxification and cytoprotective responses to cellular stress. Of clinical interest, Nrf1 mediates the proteasomal 'bounce-back' response, leading to drug resistance to proteasomal inhibitors for clinical treatment of neuroblastoma, multiple myeloma and triple-negative breast cancers (Steffen et al, 2010;Bugno et al, 2015;Sekine et al, 2018). During its translation, Nrf1 is targeted to the endoplasmic reticulum (ER) and subject to extensive post-translational modification before it regulates its target genes.…”

Section: Toxicology and Pharmacologymentioning

confidence: 99%

New insights into nuclear factor erythroid 2-related factors in toxicology and pharmacology

Hayes

Yamamoto

2019

Toxicology and Applied Pharmacology

Self Cite

View full text Add to dashboard Cite

O-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1

Abstract: Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors.

Cited by 52 publications

References 68 publications

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Functional Analysis of O-GlcNAcylation in Cancer Metastasis

New insights into nuclear factor erythroid 2-related factors in toxicology and pharmacology

Contact Info

Product

Resources

About