Modification of p27 with O-linked N-acetylglucosamine regulates cell proliferation in hepatocellular carcinoma

Qiu, Huiyuan; Liu, Fang; Tao, Tao; Zhang, Dongmei; Liu, Xiaojuan; Zhu, Guizhou; Xu, Zhiwei; Ni, Runzhou; Shen, Aiguo

doi:10.1002/mc.22490

Cited by 17 publications

(13 citation statements)

References 35 publications

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“…Cyclin-dependent protein kinase inhibitors (CKIs), which have indispensable roles in cell cycle control, can also influence the development and progression of cancer [40-42]. Because of function of SH3PXD2A-AS1 in modulating the cell cycle in CRC cells, we next examined the alterations of CKIs family members (including P15, P16, P21, P27, P57) in SW480 and DLD-1 cells with SH3PXD2A-AS1 knockdown.…”

Section: Resultsmentioning

confidence: 99%

Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer

Peng

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. Current evidence has revealed the key roles of long non-coding RNAs (IncRNAs) in multiple cancers, including CRC. In this study we identified the lncRNA SH3PXD2A-AS1 as a novel molecule associated with CRC progression by analyzing the publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to examine the expression levels of SH3PXD2A-AS1 in CRC tissue samples and CRC cell lines. Cell viability examination, colony-formation experiments, ethynyl deoxyuridine (Edu) assays and flow cytometry were performed to investigate the roles of SH3PXD2A-AS1 in CRC proliferation, cell cycle regulation, and apoptosis. Transwell assays were used to explore the effects of SH3PXD2A-AS1 on CRC cells migration and invasion. A nude mice model was used to assess the effects of SH3PXD2A-AS1 on tumorigenesis in vivo. Subcellular fractionation, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays were conducted to detect the molecular mechanisms of SH3PXD2A-ASl-mediated gene expression. Rescue assays were used to determine whether P57 and Kruppel-like factor 2 (KLF2) were involved in SH3PXD2A-ASl-dependent CRC proliferation. Results: We firstly found that SH3PXD2A-AS1 was significantly upregulated in CRC tissues and cell lines, and overexpression of SH3PXD2A-AS1 was correlated with tumor size, TNM stage, and lymph node metastasis in patients with CRC. Furthermore, SH3PXD2A-AS1 knockdown inhibited CRC cells proliferation, migration and invasion in vitro, and suppressed tumorigenesis in vivo. Mechanistic studies indicated that SH3PXD2A-AS1 could epiqenetically repress P57 and KLF2 expression through interaction with EZH2. Rescue experiments suggested that SH3PXD2A-ASl-mediated oncogenesis was impaired by overexpression of P57 or KLF2. Interestingly, the expression of SH3PXD2A-AS1 was inversely correlated with the expression of P57 and KLF2 in CRC tissue samples. Conclusion: Our research presents the first evidence that SH3PXD2A-AS1 acts as an oncogene in CRC, and may be a promising diagnostic or therapeutic target in patients with CRC.

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Section: Resultsmentioning

confidence: 99%

Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer

Peng

Zhou

et al. 2018

Cell Physiol Biochem

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“…Activation of neurons increases O-GlcNAcylation of cyclin-dependent kinase 5, blocking its binding to p53 to suppress apoptosis (198). O-GlcNAcylation of p27 blocks cyclin/CDK-p27 binding, contributing to regulation of the cell cycle (199). O-GlcNAcylation of transforming growth factor-␤-ASBMB AWARD ARTICLE: Regulation of signaling and transcription activated kinase (TAK1) regulates pro-inflammatory activation and M1 polarization of macrophages (200).…”

Section: Nutrient Regulation Of Signalingmentioning

confidence: 99%

Nutrient regulation of signaling and transcription

Hart

2019

Journal of Biological Chemistry

278

225

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O‐GlcNAc cycles on and off thousands of nucleocytoplasmic proteins and has extensive crosstalk with protein phosphorylation. O‐GlcNAc cycles on nearly all proteins involved in transcription, where it regulates gene expression in response to nutrients. O‐GlcNAc also regulates the cycling of the TATA‐binding (TBP) protein on and off DNA during the transcription cycle. Targeted, inducible, deletion of the O‐GlcNAc Transferase (OGT) in aCAMKII positive (excitatory) neurons of adult mice results in a morbidly obese mouse with a satiety defect. Thus, O‐GlcNAcylation not only serves as a nutrient sensor in all cells, but also is directly involved in appetite regulation. O‐GlcNAcylation also plays an important role in the trafficking of the AMPA receptors in neurons and in the development of functional synaptic spines. Recent studies have shown that more than one‐half of all human protein kinases are modified by O‐GlcNAc and all kinases that have been tested are indeed regulated in some way by the sugar. Abnormal O‐GlcNAcylation of CAMKII contributes directly to diabetic cardiomyopathy and to arrhythmias associated with diabetes. Prolonged elevation of O‐GlcNAc, as occurs in diabetes, contributes directly to diabetic complications and is a major mechanism of glucose toxicity. Drugs that elevate O‐GlcNAcylation in the brain, which, in‐turn, prevents hyperphosphorylation, appear to be of benefit for the treatment of Alzheimer's disease in animal models. To date, all cancers have elevated O‐GlcNAc cycling, which may play a key role in the regulation of metabolism in cancer cells. Support or Funding Information Supported by NIH P01HL107153, R01GM116891, R01DK61671, and N01‐HV‐00240. Dr. Hart receives a share of royalty received by the university on sales of the CTD 110.6 antibody, which are managed by JHU. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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“…Apart from the numerous specific cell cycle regulators, several transcription factors involved in cell proliferation control are O-GlcNAc modified, e.g. p53, c-Myc, NF-κB, FoxM1, β-catenin, and Sp1 [205,217,218], as well as the tumor-suppressor retinoblastoma (Rb) [219] and cell cycle inhibitor p27 [220]. p21 protein was not demonstrated yet to be directly influenced by O-GlcNAc, however OGT knock-down was shown to up-regulate p21 while simultaneously down-regulate Cyclin D1 [221].…”

Section: O-glcnac and Its Effect On Cell Cycle Regulationmentioning

confidence: 99%

Hyperglycemia-Induced Aberrant Cell Proliferation; A Metabolic Challenge Mediated by Protein O-GlcNAc Modification

Nagy

Fisi

Frank

et al. 2019

Cells

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Chronic hyperglycemia has been associated with an increased prevalence of pathological conditions including cardiovascular disease, cancer, or various disorders of the immune system. In some cases, these associations may be traced back to a common underlying cause, but more often, hyperglycemia and the disturbance in metabolic balance directly facilitate pathological changes in the regular cellular functions. One such cellular function crucial for every living organism is cell cycle regulation/mitotic activity. Although metabolic challenges have long been recognized to influence cell proliferation, the direct impact of diabetes on cell cycle regulatory elements is a relatively uncharted territory. Among other “nutrient sensing” mechanisms, protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification emerged in recent years as a major contributor to the deleterious effects of hyperglycemia. An increasing amount of evidence suggest that O-GlcNAc may significantly influence the cell cycle and cellular proliferation. In our present review, we summarize the current data available on the direct impact of metabolic changes caused by hyperglycemia in pathological conditions associated with cell cycle disorders. We also review published experimental evidence supporting the hypothesis that O-GlcNAc modification may be one of the missing links between metabolic regulation and cellular proliferation.

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Modification of p27 with O-linked N-acetylglucosamine regulates cell proliferation in hepatocellular carcinoma

Cited by 17 publications

References 35 publications

Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer

Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer

Nutrient regulation of signaling and transcription

Hyperglycemia-Induced Aberrant Cell Proliferation; A Metabolic Challenge Mediated by Protein O-GlcNAc Modification

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