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Review
. 2022 Jun 18;14(12):3013.
doi: 10.3390/cancers14123013.

O-GlcNAcylation: An Emerging Protein Modification Regulating the Hippo Pathway

Eunah Kim  1 , Jeong Gu Kang  2   3 , Eek-Hoon Jho  1   4 , Won Ho Yang  1   5 , Jin Won Cho  1   5
Affiliations
Review

O-GlcNAcylation: An Emerging Protein Modification Regulating the Hippo Pathway

Eunah Kim et al. Cancers (Basel). .

Abstract

The balance between cellular proliferation and apoptosis and the regulation of cell differentiation must be established to maintain tissue homeostasis. These cellular responses involve the kinase cascade-mediated Hippo pathway as a crucial regulator. Hence, Hippo pathway dysregulation is implicated in diverse diseases, including cancer. O-GlcNAcylation is a non-canonical glycosylation that affects multiple signaling pathways through its interplay with phosphorylation in the nucleus and cytoplasm. An abnormal increase in the O-GlcNAcylation levels in various cancer cells is a potent factor in Hippo pathway dysregulation. Intriguingly, Hippo pathway dysregulation also disrupts O-GlcNAc homeostasis, leading to a persistent elevation of O-GlcNAcylation levels, which is potentially pathogenic in several diseases. Therefore, O-GlcNAcylation is gaining attention as a protein modification that regulates the Hippo pathway. This review presents a framework on how O-GlcNAcylation regulates the Hippo pathway and forms a self-perpetuating cycle with it. The pathological significance of this self-perpetuating cycle and clinical strategies for targeting O-GlcNAcylation that causes Hippo pathway dysregulation are also discussed.

Keywords: Hippo pathway; O-GlcNAcylation; cancer; cellular signaling pathway.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the mammalian Hippo pathway. The Hippo kinase cascade, composed of Ser/Thr kinases MST1/2 and LATS1/2, adaptor proteins SAV1 and MOB1, and effectors YAP/TAZ, is regulated by various stimuli, including cell–cell junctions, cellular stresses, mechanical cues, and multiple extracellular signaling molecules. A “+” indicates a stimulus that increases the activity of the Hippo pathway, and a “−” indicates a stimulus that decreases activity. The Hippo pathway phosphorylates YAP/TAZ, leading to their cytoplasmic sequestration and proteasomal degradation. Dephosphorylated YAP/TAZ translocate into the nucleus and act as transcriptional cofactors, thereby controlling cellular responses such as proliferation, survival, and metastasis and affecting stemness, regeneration, organ size, and tissue homeostasis.
Figure 2
Figure 2
UDP-GlcNAc synthesis via the HBP and O-GlcNAc cycling. In the HBP, UDP-GlcNAc, an active monosaccharide donor for O-GlcNAcylation, is synthesized by consolidating glucose, glutamine, acetyl-CoA, and UTP, which are metabolites of carbohydrates, proteins, lipid acids, and nucleotides, respectively. The GlcNAc moiety of UDP-GlcNAc is transferred by OGT to the hydroxyl group of Ser/Thr residues on target proteins. O-GlcNAc from target proteins is then hydrolyzed by OGA.
Figure 3
Figure 3
Exclusive enzymes directly involved in the O-GlcNAcylation cycle. (A) The schematic structure of hOGT isoforms. Three hOGT variants (ncOGT, mOGT, and sOGT) are derived from the OGT gene located on chromosome Xq13.1 by alternative splicing and multiple transcription start sites. These variants possess an identical catalytic domain in the C-terminal region, but they have different TPR repeats involved in substrate recognition in the N-terminal region. ncOGT (116 kDa) has 13.5 TPR repeats, mOGT (103 kDa) contains 9 TPR repeats, and sOGT possesses only 2.5 TPR repeats. Additionally, only mOGT contains a mitochondrial targeting sequence (MTS) in the N-terminal region. (B) The structure of human OGA (hOGA) isoforms. Two hOGA variants (ncOGA and sOGA) are produced from the MGEA5 gene located on chromosome 10q24.32. Both contain a hydrolase catalytic domain in the N-terminal region, but only ncOGA has a HAT-like domain and part of the stalk domain. (C) The function of OGT O-GlcNAcylation. O-GlcNAcylation at Ser389 of OGT promotes interaction with importin α5, leading to the nuclear import of OGT. O-GlcNAcylation at Ser3 and Ser4 of OGT inhibits its activity by competing with GSK3β-mediated phosphorylation. (D) The function of OGA O-GlcNAcylation. O-GlcNAcylation at Ser405 of OGA represses its stability and activity.
Figure 4
Figure 4
Mechanism by which O-GlcNAcylation constantly attenuates the Hippo pathway through mutual regulation. The O-GlcNAcylation of specific proteins, such as LRP6, LATS2, YAP, and AMOT, increases the activity of the Hippo pathway effector YAP. LRP6 O-GlcNAcylation may diminish LATS activity by decreasing Merlin–LATS interactions through the inhibition of the lysosomal degradation of LRP6. LATS2 O-GlcNAcylation inhibits its activity by interrupting the MOB1–LATS2 interaction. YAP O-GlcNAcylation induces its activity by disturbing the interaction with LATS1. AMOT O-GlcNAcylation may cause the nuclear accumulation of YAP by decreasing AMOT phosphorylation at Ser175. Hyperactivated YAP induces the gene expression of LATS2, Merlin, and OGT. LATS2 O-GlcNAcylation blocks the Hippo pathway negative feedback loop caused by YAP-mediated LATS2/Merlin gene expression by blocking MOB1-LATS2 interactions. As a result, abnormally increased O-GlcNAcylation induces Hippo pathway dysregulation and sustains aberrant hyper-O-GlcNAcylation.
Figure 5
Figure 5
The schematic model of O-GlcNAcylation regulating the Hippo pathway through other pathways that crosstalk with the Hippo pathway. The O-GlcNAcylation of β-catenin, a mediator of the canonical Wnt signaling pathway, competes with ubiquitinylation-inducing β-catenin phosphorylation, which may stabilize β-catenin and TAZ and promote β-catenin/TCF4 complex-mediated YAP expression. Smad4 O-GlcNAcylation enhances the TGF-β/SMAD signaling pathway, which can upregulate SnoN gene expression, thereby inactivating LATS1/2 by stabilizing Smad4. PKC O-GlcNAcylation is possibly related to TGF-β signaling in a way that TGFβRII expression is decreased by reducing PKC activities. In Gαs-coupled GPCR signaling, PKA O-GlcNAcylation may enhance LATS1/2 activity by increasing PKA-mediated LATS1/2 phosphorylation or inhibiting actin fiber formation. NOTCH1 O-GlcNAcylation elicits the release of NICD, which can stabilize YAP/TAZ, by enhancing the interaction between NOTCH1 and DLL1 or DLL4.
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