O-GlcNAcylation promotes cerebellum development and medulloblastoma oncogenesis via SHH signaling

Chen, Liping; Liu, Ying; Song, Zhihong; Xue, Saisai; Liu, Fengjiao; Chang, Xin; Wu, Yan; Duan, Xiaotao; Wu, Haitao

doi:10.1073/pnas.2202821119

Cited by 22 publications

(22 citation statements)

References 79 publications

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“…The presence of this PTM on diverse proteins is consistent with its emergence as a regulator of numerous cellular pathways ranging from transcription [1] and translation [2, 3] through to participating in cell signaling [4, 5] . Given these molecular roles, it is unsurprising that O‐GlcNAc is implicated in a range of physiological processes ranging, for example, from stress response [6] to nutrient sensing [4, 7] . Remarkably, the modification of proteins with O‐GlcNAc is principally controlled by just two enzymes.…”

Section: Introductionmentioning

confidence: 73%

Potent De Novo Macrocyclic Peptides That Inhibit O‐GlcNAc Transferase through an Allosteric Mechanism

et al. 2022

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Glycosyltransferases are a superfamily of enzymes that are notoriously difficult to inhibit. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non-standard peptides integrated discovery) system, to identify macrocyclic peptides with high binding affinities for O-GlcNAc transferase (OGT). These macrocycles inhibit OGT activity through an allosteric mechanism that is driven by their binding to the tetratricopeptide repeats of OGT. Saturation mutagenesis in a maturation screen using 39 amino acids, including 22 non-canonical residues, led to an improved unnatural macrocycle that is � 40 times more potent than the parent compound (K i app = 1.5 nM). Subsequent derivatization delivered a biotinylated derivative that enabled one-step affinity purification of OGT from complex samples. The high potency and novel mechanism of action of these OGT ligands should enable new approaches to elucidate the specificity and regulation of OGT.

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Section: Introductionmentioning

confidence: 73%

Potent De Novo Macrocyclic Peptides That Inhibit O‐GlcNAc Transferase through an Allosteric Mechanism

et al. 2022

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“…To test whether decreasing O-GlcNAc in aged mice can restore spermatogenesis, we used the enzymatic OGT inhibitor OSMI-1, which was previously reported to be suitable for long-term use without side effects in a mouse model (25). After intraperitoneal administration of 10 mg/kg OSMI-1 in aged mice for 35 consecutive days (Fig.…”

Section: 7mentioning

confidence: 99%

Age-related elevation of O-GlcNAc causes meiotic arrest and subfertility in male mice

Yao

Zhang

et al. 2023

Preprint

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In recent years, the postponement of childbearing has become a critical social issue. Male fertility is negatively associated with age because of testis aging. Spermatogenesis is impaired with age, but the molecular mechanism remains unknown. The dynamic posttranslational modification O-linked N-acetylglucosamine (O-GlcNAc), which is a type of monosaccharide modification, has been shown to drive the process of aging in various systems, but it has not yet been investigated in the testis and male reproductive aging. Thus, this study aims to investigate the alteration of O-GlcNAc with aging and explore the role of O-GlcNAc in spermatogenesis. Here, we demonstrate that the decline in spermatogenesis in aged mice is associated with elevation of O-GlcNAc. O-GlcNAc is specifically localized in differentiating spermatogonia and spermatocytes, indicating its crucial role in meiotic initiation and progression. Mimicking the age-related elevation of O-GlcNAc in young mice by disabling O-GlcNAcase (OGA) using the chemical inhibitor Thiamet-G can recapitulate the impairment of spermatogenesis in aged mice. Mechanistically, the elevation of O-GlcNAc in the testis leads to meiotic pachytene arrest due to defects in synapsis and recombination. Furthermore, decreasing O-GlcNAc in aged testes using an O-GlcNAc transferase (OGT) inhibitor can partially rescue the age-related impairment of spermatogenesis. Our results highlight that O-GlcNAc, as a novel posttranslational modification, participates in meiotic progression and drives the impairment of spermatogenesis during aging.

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“…Specifically, elevated OGT in GBM cells increases the phosphorylation of ACSS2 at Ser267 in a CDK5-dependent manner, thereby reducing polyubiquitination and degradation to increase its stability. Chen et al (Chen et al 2022 ) observed the elevated O -GlcNAc levels in human samples of Sonic hedgehog (Shh)-subtype medulloblastoma and revealed that OGT in granule neuron precursors (GNPs) may contribute to medulloblastoma oncogenesis by activating the Shh signaling pathway via O -GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2). These studies reveal the important role of O -GlcNAc signaling in brain cancer and deserve further exploration.…”

Section: O -Glcnac and Cancermentioning

confidence: 99%

O-GlcNAcylation: an important post-translational modification and a potential therapeutic target for cancer therapy

Zhang

Liang

et al. 2022

Mol Med

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O-linked β-d-N-acetylglucosamine (O-GlcNAc) is an important post-translational modification of serine or threonine residues on thousands of proteins in the nucleus and cytoplasm of all animals and plants. In eukaryotes, only two conserved enzymes are involved in this process. O-GlcNAc transferase is responsible for adding O-GlcNAc to proteins, while O-GlcNAcase is responsible for removing it. Aberrant O-GlcNAcylation is associated with a variety of human diseases, such as diabetes, cancer, neurodegenerative diseases, and cardiovascular diseases. Numerous studies have confirmed that O-GlcNAcylation is involved in the occurrence and progression of cancers in multiple systems throughout the body. It is also involved in regulating multiple cancer hallmarks, such as metabolic reprogramming, proliferation, invasion, metastasis, and angiogenesis. In this review, we first describe the process of O-GlcNAcylation and the structure and function of O-GlcNAc cycling enzymes. In addition, we detail the occurrence of O-GlcNAc in various cancers and the role it plays. Finally, we discuss the potential of O-GlcNAc as a promising biomarker and novel therapeutic target for cancer diagnosis, treatment, and prognosis.

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O-GlcNAcylation promotes cerebellum development and medulloblastoma oncogenesis via SHH signaling

Cited by 22 publications

References 79 publications

Potent De Novo Macrocyclic Peptides That Inhibit O‐GlcNAc Transferase through an Allosteric Mechanism

Potent De Novo Macrocyclic Peptides That Inhibit O‐GlcNAc Transferase through an Allosteric Mechanism

Age-related elevation of O-GlcNAc causes meiotic arrest and subfertility in male mice

O-GlcNAcylation: an important post-translational modification and a potential therapeutic target for cancer therapy

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