O-GlcNAcylation promotes pancreatic tumor growth by regulating malate dehydrogenase 1

Zhu, Qiang; Zhou, Hong; Wu, Liming; Lai, Zhenyuan; Geng, Didi; Yang, Weiwei; Zhang, Jie; Fan, Zhiya; Qin, Weijie; Wang, Yong; Zhou, Ruhong

doi:10.1038/s41589-022-01085-5

Cited by 45 publications

(26 citation statements)

References 41 publications

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“…Moreover, KRAS G12D in PDAC cells could also positively regulate the glutamine catabolic pathway by upregulating the O- GlcNAcylation of malate dehydrogenase 1 (MDH1), the expression of which was significantly elevated in clinical PDAC samples. This finding demonstrated that O- GlcNAcylation may also be related to signaling pathways involving KRAS mutation and glutamine metabolism in PDAC ( Zhu et al, 2022 ) ( Figure 5 ).…”

Section: Kras Mutation In Pdac Development and Progressionmentioning

confidence: 89%

KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression

Zhang

Xiang

et al. 2023

Front. Cell Dev. Biol.

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Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It has a poor response to conventional therapy and has an extremely poor 5-year survival rate. PDAC is driven by multiple oncogene mutations, with the highest mutation frequency being observed in KRAS. The KRAS protein, which binds to GTP, has phosphokinase activity, which further activates downstream effectors. KRAS mutation contributes to cancer cell proliferation, metabolic reprogramming, immune escape, and therapy resistance in PDAC, acting as a critical driver of the disease. Thus, KRAS mutation is positively associated with poorer prognosis in pancreatic cancer patients. This review focus on the KRAS mutation patterns in PDAC, and further emphases its role in signal transduction, metabolic reprogramming, therapy resistance and prognosis, hoping to provide KRAS target therapy strategies for PDAC.

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Section: Kras Mutation In Pdac Development and Progressionmentioning

confidence: 89%

KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression

Zhang

Xiang

et al. 2023

Front. Cell Dev. Biol.

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“…Previously MD has been employed to predict glycoengineering of GPCRs with O-GlcNAc, and the simulation suggests that the modification would enhance proteolytic stability (40). A recent work on malate dehydrogenase 1 (MDH1) with MD indicates that O-GlcNAc strengthens MDH1-substrate binding, probably as a molecular glue (41). When chemical synthesis does succeed, it no doubt pinpoints the exact role of O-GlcNAc on the specific protein or peptide.…”

Section: Discussionmentioning

confidence: 99%

DNA damage-induced YTHDC1 O-GlcNAcylation promotes homologous recombination by enhancing N6-methyladenosine binding

Yuan

et al. 2022

Preprint

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N6-methyladenosine (m6A) is the most prevalent RNA modification, and its regulators include writers, readers and erasers. m6A is under stringent control and takes part in many biological events, but it is not known whether there is an interplay between m6A and glycosylation. Here we investigated an m6A reader, YTHDC1, which has been shown to be recruited to the DNA-RNA hybrid at DNA damage sites and regulate homologous recombination (HR) during DNA damage repair. We found that YTHDC1 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification at Ser396 upon DNA damage, which is pivotal for YTHDC1 chromatin binding and ionization radiation induced foci (IRIF) formation. RNA immunoprecipitation (RIP) and molecular dynamics (MD) simulations indicate that O-GlcNAcylation is vital for YTHDC1 to bind with m6A RNA. Fluorescence recovery after photo bleaching (FRAP) analysis revealed that YTHDC1 O-GlcNAcylation is essential for DNA damage-induced YTHDC1-m6A condensate formation. We further demonstrate that YTHDC1 O-GlcNAcylation promotes HR-mediated DNA damage repair and cell survival, probably through recruitment of Rad51 to the damage sites. We propose that YTHDC1 O-GlcNAcylation is instrumental for HR and genome stability.

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“…Most glycans exist on the surface of cells and secreted proteins, with intricate and varied structures 1071–1073 . In contrast, the types of glycosylation existing in the nucleus and cytoplasm have simple structures and are highly dynamic 1074,1075 . The structural diversity and extensive distribution of protein glycosylation make it one of the most prevalent forms of PTMs in humans 1076 …”

Section: Glycosylationmentioning

confidence: 99%

“…[1071][1072][1073] In contrast, the types of glycosylation existing in the nucleus and cytoplasm have simple structures and are highly dynamic. 1074,1075 The structural diversity and extensive distribution of protein glycosylation make it one of the most prevalent forms of PTMs in humans. 1076 Protein glycosylation is a complicated process that involves multiple steps.…”

Section: Glycosylationmentioning

confidence: 99%

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Zhong

Xiao

Xie

et al. 2023

MedComm

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Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

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O-GlcNAcylation promotes pancreatic tumor growth by regulating malate dehydrogenase 1

Cited by 45 publications

References 41 publications

KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression

KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression

DNA damage-induced YTHDC1 O-GlcNAcylation promotes homologous recombination by enhancing N6-methyladenosine binding

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

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