Identification of UAP1L1 as a critical factor for protein O-GlcNAcylation and cell proliferation in human hepatoma cells

Lai, Ching-Yu; Liu, Hsuan; Tin, Kai Xuan; Huang, Yi; Yeh, Kun-Hai; Peng, Hubert W; Chen, Huan-Da; He, Junyu; Chiang, Yuang-Chin; Liu, Chun‐Shan; Weng, Shih‐Yen; Tao, Mi‐Hua; Yen, J. J.; Yang-Yen, Hsin-Fang

doi:10.1038/s41388-018-0442-6

Cited by 26 publications

(29 citation statements)

References 36 publications

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“…UAP1L1 (UDP- N -acetylglucosamine pyrophosphorylase 1 like 1) appears to be a regulator of O-GlcNAc transferase function and is a critical factor for cell proliferation in human hepatocarcinoma cells [73]. UAP1L1 is significantly upregulated in a distinct subset of HCC tissues, and patients with upregulated expression of UAP1L1 appeared to have a poor prognosis [73].…”

Section: Resultsmentioning

confidence: 99%

Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling

Gerresheim

Bathke

Michel

et al. 2019

IJMS

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Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known. Methods: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days. Results: Established viral replication does not cause global changes in host gene expression—only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes. Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here.

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Section: Resultsmentioning

confidence: 99%

Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling

Gerresheim

Bathke

Michel

et al. 2019

IJMS

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“…Moreover, their investigations further suggested that UAP1 could block the influence of Nlinked glycosylation inhibitor on prostate cancer cells, which could be re-sensitized after silencing UAP1 [31]. UAP1L1 is another protein with 59% sequences identity to UAP1 [32]. The studies of Yang-Yen et al indicated that, despite of the structural similarity between UAP1 and UAP1L1, they possess distinctly different functions in the synthesis of UDP-GlcNAc.…”

Section: Discussionmentioning

confidence: 99%

“…The studies of Yang-Yen et al indicated that, despite of the structural similarity between UAP1 and UAP1L1, they possess distinctly different functions in the synthesis of UDP-GlcNAc. Moreover, their studies also demonstrated the overexpression of UAP1L1 in HCC tissues compared with normal tissues and elucidated the promotion or inhibition of HCC development in vitro and in vivo by UAP1L1 overexpression or knockdown [32]. In spite of these, the role of UAP1L1 in human cancers, especially gastric cancer and the underlying mechanism are still not clear.…”

Section: Discussionmentioning

confidence: 99%

Identification of UAP1L1 as tumor promotor in gastric cancer through regulation of CDK6

Liu

et al. 2020

Aging

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Gastric cancer (GC) is one of the most commonly diagnosed malignancies in digestive tract and its underlying molecular mechanism is still not clear, so we aimed to reveal the relationship between GC and UDP-GlcNAc pyrophosphorylase-1 like 1 (UAP1L1). The detection of UAP1L1 expression in GC tumor and normal tissues was accomplished by immunohistochemistry and demonstrated the upregulation of UAP1L1 in GC, which was statistically associated with tumor grade. GC cell models constructed via transfection of UAP1L1-silencing/ overexpressing lentiviruses were employed for evaluating the effects of UAP1L1 knockdown/overexpression on GC in vitro and in vivo. The results indicated that UAP1L1 played important role in development of GC through regulating cell proliferation, colony formation, cell apoptosis and cell migration. Subsequently, CDK6 was identified as a potential target in UAP1L1 induced regulation of GC, downregulation of which exhibited similar inhibition effects on GC with UAP1L1. Moreover, it was demonstrated that the promotion of GC by UAP1L1 overexpression could be significantly attenuated or even reversed by simultaneously silencing CDK6. In conclusion, UAP1L1 was reported to be a tumor promotor in the development and progression of GC which may exert its role through regulating CDK6 and may act as a candidate of therapeutic target in treatment.

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“…does not efficiently catalyze UDP-GlcNAc synthesis, but instead interacts directly with the Cterminal catalytic domain of OGT. Knockdown of UAP1L1 markedly reduced global O-GlcNAcylation in HepG2 and TONG cells, yet UAP1L1 alone is not sufficient to bolster OGT activity in vitro [44]. Thus, UAP1L1 likely maintains OGT activity within cells through direct binding, though more detailed characterization is necessary.…”

Section: Post-translational Modificationsmentioning

confidence: 99%

“…UDP-N-acetylglucosamine pyrophosphorylase-1 (UAP1) catalyzes the last step in the synthesis of UDP-GlcNAc. A UAP1 paralog, UAP1-like-1 (UAP1L1), is required for OGT mediated protein O-GlcNAcylation in HepG2 liver hepatocellular carcinoma cells [44]. Surprisingly, UAP1L1…”

Section: Post-translational Modificationsmentioning

confidence: 99%

Molecular mechanisms regulating O-linked N-acetylglucosamine (O-GlcNAc)–processing enzymes

King

Males

Davies

et al. 2019

Current Opinion in Chemical Biology

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The post-translational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) dynamically programs cellular physiology to maintain homeostasis and tailor biochemical pathways to meet context-dependant cellular needs. Despite diverse roles for O-GlcNAc, only two enzymes act antagonistically to govern its cycling; O-GlcNAc transferase (OGT) installs the monosaccharide on target proteins and O-GlcNAc hydrolase (OGA) removes it. Recent literature has exposed a network of mechanisms regulating these two enzymes to choreograph global, and target-specific, O-GlcNAc cycling in response to cellular stress and nutrient availability. Herein, we amalgamate these emerging mechanisms from a structural and molecular perspective to explore how the cell exerts fine control to regulate O-GlcNAcylation of diverse proteins in a selective fashion. Papers of particular interest, published within the period of review, have been highlighted as: *of special interest ** of outstanding interest **[3] An important paper in the field. The authors provide unambiguous evidence for mutations in ogt implicated in XLID influencing OGT function. Despite largely normal global O-GlcNAc levels, significant changes in gene transcription are observed. Furthermore, a compensatory mechanism to maintain global O-GlcNAc levels involving OGT-mSin3A-HDAC1 dependant transcriptional repression at the OGA promoter is proposed. *[6] The authors develop a systematic platform for glycosylation sequence characterization and optimization and use this method to characterize OGT sequence preference. This analysis revealed a surprising preference for an aromatic residue at the-4 subsite. *[10] An asparagine ladder in the TPR domains mediates OGT interaction with protein substrates. * [12] New chemical biology tools to identify features of OGT responsible for substrate targeting. This method uncovered a patch of residues lining the inner surface of the N-terminal domain that contribute to interaction with multiple substrates. **[13] A nice structural study defines the effect of XLID-associated OGT mutation L254F as distorting the TPR helix. * [27] mOGT was shown to be catalytically active in vivo and plays an important role in supporting mitochondrial structure and function. **[28] A fundamental advance in discovery of the OGT NLS and the effects of S389 O-GlcNAcylation and interaction with importin α5 for nuclear import. *[35] The authors demonstrate that OGT is enriched in the post-synaptic density of excitatory neuronal synapses whereby it regulates synapse maturation. *[37] Upon glucagon-induced calcium signalling CamKII phosphorylates OGT at S20, which induces O-GlcNAc modification of Ulk proteins through potentiation of AMPKdependant phosphorylation. **[38] Chk1 phosphorylates OGT S20, and this modification regulates OGT localization to the mid-body and regulation of vimentin bridge formation and severing during mitosis. *[39] LSD2 was shown to act as an E3 ligase to ubiquitinylate OGT and thereby facilitate its UPS mediated degradation. **[43] Circad...

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Identification of UAP1L1 as a critical factor for protein O-GlcNAcylation and cell proliferation in human hepatoma cells

Cited by 26 publications

References 36 publications

Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling

Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling

Identification of UAP1L1 as tumor promotor in gastric cancer through regulation of CDK6

Molecular mechanisms regulating O-linked N-acetylglucosamine (O-GlcNAc)–processing enzymes

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