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1.
Article in English | WPRIM | ID: wpr-922251

ABSTRACT

In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.


Subject(s)
Animals , DNA Methylation , Epigenesis, Genetic , Humans , Neurodegenerative Diseases/genetics , Parkinson Disease/genetics , Protein Processing, Post-Translational
2.
Chinese Journal of Biotechnology ; (12): 3915-3932, 2021.
Article in Chinese | WPRIM | ID: wpr-921476

ABSTRACT

Targeted protein degradation (TPD) technology facilitates specific and efficient degradation of disease-related proteins through hijacking the two major protein degradation systems in mammalian cells: ubiquitin-proteasome system and lysosome pathway. Compared with traditional small molecule-inhibitors, TPD-based drugs exhibit the characteristics of a broader target spectrum. Compared with techniques interfere with protein expression on the gene and mRNA level, TPD-based drugs are target-specific, efficaciously rapid, and not constrained by post-translational modification of proteins. In the past 20 years, various TPD-based technologies have been developed. Most excitingly, two TPD-based therapeutic drugs have been approved by FDA for phase Ⅰ clinical trials in 2019. Despite of the early stage characteristics and various obstructions of the TPD technology, it could serve as a powerful tool for the development of novel drugs. This review summarizes the advances of different degradation systems based on TPD technologies and their applications in disease therapy. Moreover, the advantages and challenges of various technologies were discussed systematically, with the aim to provide theoretical guidance for further application of TPD technologies in scientific research and drug development.


Subject(s)
Animals , Proteasome Endopeptidase Complex/metabolism , Protein Processing, Post-Translational , Proteins/metabolism , Proteolysis , Technology
3.
Acta Physiologica Sinica ; (6): 980-990, 2021.
Article in Chinese | WPRIM | ID: wpr-921303

ABSTRACT

The normal development of follicles involves a series of complex life processes such as ordered transcriptional activation and inhibition, which is crucial for female reproductive ability. Histone methylation can change the chromatin state in cells and affect the transcription activity of genes. Current studies indicate that epigenetic modifications such as histone methylation play an important regulatory role in follicular development in female mammals. This paper summarized the relationship between H3K4, H3K9 methylation and germ cell development, their regulatory effects, including their dynamical changes during follicular development, and the progress of H3K4me3 and other histone methylation binding to promoter regions of different genes to regulate gene expression and thus affect germ cell epigenetic reprogramming, oocyte transcription, meiosis and other processes. This review will provide a reference for the study of mechanisms related to histone methylation modification and the development and maturation of gonadal parenchymal cells.


Subject(s)
Animals , DNA Methylation , Epigenesis, Genetic , Female , Histones , Mammals , Ovarian Follicle/growth & development , Protein Processing, Post-Translational
4.
Protein & Cell ; (12): 29-38, 2021.
Article in English | WPRIM | ID: wpr-880916

ABSTRACT

Prostate cancer is the most commonly diagnosed non-cutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions.


Subject(s)
Amino Acid Sequence , Epigenesis, Genetic , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Hepatocyte Nuclear Factor 3-alpha/metabolism , Histone Demethylases/metabolism , Histones/metabolism , Humans , Male , Mutation , Prostate/pathology , Prostatic Neoplasms/pathology , Protein Binding , Protein Processing, Post-Translational , Receptors, Androgen/metabolism , Signal Transduction , Transcription, Genetic
5.
Article in Chinese | WPRIM | ID: wpr-878883

ABSTRACT

Nano-LC MS/MS was used to analyze trypsin digested deer-hide gelatin(DHG) samples, hydroxylation and O-glycosylation on lysine sites of DHG were comprehensive identified by using PEAKS Studio software. The sites, sorts and amounts of hydroxylation and O-glycosylation on Type Ⅰ collagen α1 chain(COL1 A1) and α2 chain(COL1 A2) of DHG were revealed. As a result, 5 284 peptides were identified from DHG samples, which were mainly from COL1 A1 and COL1 A2. Among these peptides, there were 449 peptides with hydroxylysine, 442 with galactosyl-hydroxylysine, 449 with glucosyl-galactosyl-hydroxylysine. The major modified sites of hydroxylation and O-glycosylation in DHG were shown as follow: α1-9 N and α2-5 N in N-telopeptides, α1-87, α1-174, α1-930, α2-87, α2-174, α2-933 in triple helix domain, and α1-16 C in C-telopeptides. These hydroxylation and O-glycosylation were correlated with the formation and stability of collagen molecules and collagen fibrils. It is feasible for the collagens and peptides dissolving from deer skin collagen fibrils under high temperature and pressure decocting, high temperature and pressure also might destroy inter-molecular covalent cross-linking and help those glycol-peptides formations. The present study provided ideas and strategies for the in-depth investigation on DHG chemical constituents, and showed good theoretical significance and application value.


Subject(s)
Animals , Deer/metabolism , Gelatin , Glycosylation , Hydroxylation , Lysine/metabolism , Protein Processing, Post-Translational , Tandem Mass Spectrometry
6.
Article in English | WPRIM | ID: wpr-880485

ABSTRACT

Ubiquitination, an essential post-transcriptional modification (PTM), plays a vital role in nearly every biological process, including development and growth. Despite its functions in plant reproductive development, its targets in rice panicles remain unclear. In this study, we used proteome-wide profiling of lysine ubiquitination in rice (O. sativa ssp. indica) young panicles. We created the largest ubiquitinome dataset in rice to date, identifying 1638 lysine ubiquitination sites on 916 unique proteins. We detected three conserved ubiquitination motifs, noting that acidic glutamic acid (E) and aspartic acid (D) were most frequently present around ubiquitinated lysine. Enrichment analysis of Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of these ubiquitinated proteins revealed that ubiquitination plays an important role in fundamental cellular processes in rice young panicles. Interestingly, enrichment analysis of protein domains indicated that ubiquitination was enriched on a variety of receptor-like kinases and cytoplasmic tyrosine and serine-threonine kinases. Furthermore, we analyzed the crosstalk between ubiquitination, acetylation, and succinylation, and constructed a potential protein interaction network within our rice ubiquitinome. Moreover, we identified ubiquitinated proteins related to pollen and grain development, indicating that ubiquitination may play a critical role in the physiological functions in young panicles. Taken together, we reported the most comprehensive lysine ubiquitinome in rice so far, and used it to reveal the functional role of lysine ubiquitination in rice young panicles.


Subject(s)
Acetylation , Lysine/metabolism , Oryza/metabolism , Plant Proteins/metabolism , Protein Interaction Maps , Protein Processing, Post-Translational , Proteome/metabolism , Ubiquitin/metabolism , Ubiquitination
7.
Article in English | WPRIM | ID: wpr-880483

ABSTRACT

Protein lysine methylation is a prevalent post-translational modification (PTM) and plays critical roles in all domains of life. However, its extent and function in photosynthetic organisms are still largely unknown. Cyanobacteria are a large group of prokaryotes that carry out oxygenic photosynthesis and are applied extensively in studies of photosynthetic mechanisms and environmental adaptation. Here we integrated propionylation of monomethylated proteins, enrichment of the modified peptides, and mass spectrometry (MS) analysis to identify monomethylated proteins in Synechocystis sp. PCC 6803 (Synechocystis). Overall, we identified 376 monomethylation sites in 270 proteins, with numerous monomethylated proteins participating in photosynthesis and carbon metabolism. We subsequently demonstrated that CpcM, a previously identified asparagine methyltransferase in Synechocystis, could catalyze lysine monomethylation of the potential aspartate aminotransferase Sll0480 both in vivo and in vitro and regulate the enzyme activity of Sll0480. The loss of CpcM led to decreases in the maximum quantum yield in primary photosystem II (PSII) and the efficiency of energy transfer during the photosynthetic reaction in Synechocystis. We report the first lysine monomethylome in a photosynthetic organism and present a critical database for functional analyses of monomethylation in cyanobacteria. The large number of monomethylated proteins and the identification of CpcM as the lysine methyltransferase in cyanobacteria suggest that reversible methylation may influence the metabolic process and photosynthesis in both cyanobacteria and plants.


Subject(s)
Bacterial Proteins/metabolism , Lysine/metabolism , Methyltransferases/metabolism , Photosynthesis , Protein Processing, Post-Translational , Synechocystis/growth & development
8.
Article in English | WPRIM | ID: wpr-811061

ABSTRACT

PURPOSE: Reduction-oxidation reaction homeostasis is vital for regulating inflammatory conditions and its dysregulation may affect the pathogenesis of chronic airway inflammatory diseases such as asthma. Peroxiredoxin-6, an important intracellular anti-oxidant molecule, is reported to be highly expressed in the airways and lungs. The aim of this study was to analyze the expression pattern of peroxiredoxin-6 in the peripheral blood mononuclear cells (PBMCs) of asthmatic patients and in bronchial epithelial cells (BECs).METHODS: The expression levels and modifications of peroxiredoxin-6 were evaluated in PBMCs from 22 asthmatic patients. Phosphorylated and acetylated peroxiredoxin-6 in hydrogen peroxide-treated human BECs was detected using immunoprecipitation analysis. The expression level of peroxiredoxin-6 was also investigated in BECs treated with hydrogen peroxide. Cycloheximide and proteasome inhibitors were used to determine whether peroxiredoxin-6 is degraded by proteasomes.RESULTS: Peroxiredoxin-6 expression was significantly reduced in the PBMCs of asthmatic patients compared to control subjects. Distinct modification patterns for peroxiredoxin-6 were observed in the PBMCs of asthmatic patients using 2-dimensional-electrophoresis. The levels of phosphorylated serine and acetylated lysine in peroxiredoxin-6 were significantly increased in the BECs following hydrogen peroxide treatment. The level of peroxiredoxin-6 expression was reduced in hydrogen peroxide-stimulated BECs, presumably due to proteasomes.CONCLUSIONS: The expression of peroxiredoxin-6, which is down-regulated in the immune cells of asthmatic patients and BECs, can be modified by oxidative stress. This phenomenon may have an effect on asthmatic airway inflammation.


Subject(s)
Asthma , Cycloheximide , Epithelial Cells , Homeostasis , Humans , Hydrogen , Hydrogen Peroxide , Immunoprecipitation , Inflammation , Lung , Lysine , Oxidative Stress , Proteasome Inhibitors , Protein Processing, Post-Translational , Serine
9.
Article in Chinese | WPRIM | ID: wpr-878682

ABSTRACT

Proteins exert their roles in life activities via post-translational modifications(PTMs),which include phosphorylation,acetylation,ubiquitination,glycosylation,and methylation.These modifications can change the functions of proteins and play key roles in a variety of diseases.Endometriosis is a common disease in women of childbearing age,although its molecular mechanisms remain unclear.Recent studies have shown that PTMs may be involved in the pathogenesis of endometriosis.Here we review the roles of PTMs in the occurrence and development of endometriosis and the potential medical treatments.


Subject(s)
Acetylation , Endometriosis/pathology , Female , Glycosylation , Humans , Phosphorylation , Protein Processing, Post-Translational , Ubiquitination
11.
Article in English | WPRIM | ID: wpr-786079

ABSTRACT

In type 2 diabetes (T2D), the leading cause of death is cardiovascular complications. One mechanism contributing to cardiac pathogenesis is alterations in metabolism, with the diabetic heart exhibiting increased fatty acid oxidation and reduced glucose utilisation. The processes classically thought to underlie this metabolic shift include the Randle cycle and changes to gene expression. More recently, alternative mechanisms have been proposed, most notably, changes in post-translational modification of mitochondrial proteins in the heart. This increased understanding of how metabolism is altered in the diabetic heart has highlighted new therapeutic targets, with an aim to improve cardiac function in T2D. This review focuses on metabolism in the healthy heart and how this is modified in T2D, providing evidence for the mechanisms underlying this shift. There will be emphasis on the current treatments for the heart in diabetes, alongside efforts for metabocentric pharmacological therapies.


Subject(s)
Cause of Death , Gene Expression , Glucose , Heart , Metabolism , Mitochondrial Proteins , Protein Processing, Post-Translational
12.
Article in English | WPRIM | ID: wpr-763366

ABSTRACT

Vaccination is one of the most successful strategies to prevent diseases caused by pathogens. Although various expression systems including Escherichia coli, yeast, insect, and mammalian cells are currently used for producing many of vaccines, these conventional platforms have the limitation of post-translational modification, high cost, and expensive scalability. In this respect, the plant-based expression system has been considered as an attractive platform to produce recombinant vaccines due to fast, cost-effective and scalable production as well as safety. This review discusses the development of plant-derived vaccines and the current stage of plant-based expression system.


Subject(s)
Antibodies , Efficiency , Escherichia coli , Humans , Insecta , Plants , Plants, Genetically Modified , Protein Processing, Post-Translational , Vaccination , Vaccines , Vaccines, Synthetic , Yeasts
13.
Journal of Experimental Hematology ; (6): 1696-1700, 2019.
Article in Chinese | WPRIM | ID: wpr-775663

ABSTRACT

Abstract  The promyelocytic leukemia (PML) gene encoded PML protein as a tumor suppressor protein, plays important roles in the occurrence and development of various cancers including acute promyelocytic leukemia. Recent studies have indicated that there are a variety of post-translational modifications of the PML protein, such as SUMOylation, ubiquitination, phosphorylation, and acetylation in cells. These modifications of the PML protein can directly affect the formation of PML nuclear bodies (PML-NBs), repair DNA damage, and modulate cell apoptosis. Furthermore, the abnormal modifications of PML not only result in the occurrence of hematopoietic tumors, but also are closely related to the drug-resistance of cancer. Therefore, investigating the post-translational modifications of PML is significant to uncover the mechanism of formation and functions of PML-NBs, thus contributing to the prevention and treatment of related hematopoietic tumors. In this review, the characteristics of the post-translational modifications of PML protein and the relationship between these modifications and functions of PML-NBs are summarized so as to provide the potential targets for the treatment of related cancers.


Subject(s)
Humans , Intranuclear Inclusion Bodies , Leukemia, Promyelocytic, Acute , Nuclear Proteins , Promyelocytic Leukemia Protein , Protein Processing, Post-Translational
14.
Chinese Journal of Biotechnology ; (12): 741-748, 2019.
Article in Chinese | WPRIM | ID: wpr-771336

ABSTRACT

Proteomics is a fast-growing discipline that aims at systematic identification, quantification of proteins and their post-translational modifications in cells. Mass spectrometry-based shotgun proteomics technology is currently one of the mainstream methods for proteomics research. With this method, proteins need to be digested to peptides by site-specific proteases before they can be detected with mass spectrometry. Therefore, site-specific proteases played key roles in this process and so far, a variety of specific proteases have been developed and used in proteomics study. Particularly, the identification, characterization and development of proteases that cleave at the N-termini of corresponding amino acid residues, which are just mirrors to those of typical C-termini proteases, provide novel tools for proteomics analysis. In this review, we summarized the proprieties of LysargiNase, a most recently identified mirror trypsin, and its applications in proteomics research to promote its more widespread usage.


Subject(s)
Mass Spectrometry , Metalloproteases , Chemistry , Metabolism , Protein Processing, Post-Translational , Proteomics , Trypsin , Chemistry
15.
Article in English | WPRIM | ID: wpr-716320

ABSTRACT

Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseases, and cancers. Dysfunction occurs in part because of altered regulation of the mitochondrial pyruvate dehydrogenase complex (PDC), which acts as a central metabolic node that mediates pyruvate oxidation after glycolysis and fuels the Krebs cycle to meet energy demands. Fine-tuning of PDC activity has been mainly attributed to post-translational modifications of its subunits, including the extensively studied phosphorylation and de-phosphorylation of the E1α subunit of pyruvate dehydrogenase (PDH), modulated by kinases (pyruvate dehydrogenase kinase [PDK] 1-4) and phosphatases (pyruvate dehydrogenase phosphatase [PDP] 1-2), respectively. In addition to phosphorylation, other covalent modifications, including acetylation and succinylation, and changes in metabolite levels via metabolic pathways linked to utilization of glucose, fatty acids, and amino acids, have been identified. In this review, we will summarize the roles of PDC in diverse tissues and how regulation of its activity is affected in various metabolic disorders.


Subject(s)
Acetylation , Amino Acids , Citric Acid Cycle , Diabetes Mellitus, Type 2 , Fatty Acids , Glucose , Glycolysis , Metabolic Diseases , Metabolic Networks and Pathways , Metabolism , Mitochondria , Neurodegenerative Diseases , Obesity , Oxidative Phosphorylation , Oxidoreductases , Phosphoric Monoester Hydrolases , Phosphorylation , Phosphotransferases , Protein Processing, Post-Translational , Pyruvate Dehydrogenase Complex , Pyruvic Acid
16.
Article in English | WPRIM | ID: wpr-772982

ABSTRACT

Various posttranslational modifications (PTMs) participate in nearly all aspects of biological processes by regulating protein functions, and aberrant states of PTMs are frequently implicated in human diseases. Therefore, an integral resource of PTM-disease associations (PDAs) would be a great help for both academic research and clinical use. In this work, we reported PTMD, a well-curated database containing PTMs that are associated with human diseases. We manually collected 1950 known PDAs in 749 proteins for 23 types of PTMs and 275 types of diseases from the literature. Database analyses show that phosphorylation has the largest number of disease associations, whereas neurologic diseases have the largest number of PTM associations. We classified all known PDAs into six classes according to the PTM status in diseases and demonstrated that the upregulation and presence of PTM events account for a predominant proportion of disease-associated PTM events. By reconstructing a disease-gene network, we observed that breast cancers have the largest number of associated PTMs and AKT1 has the largest number of PTMs connected to diseases. Finally, the PTMD database was developed with detailed annotations and can be a useful resource for further analyzing the relations between PTMs and human diseases. PTMD is freely accessible at http://ptmd.biocuckoo.org.


Subject(s)
Databases, Protein , Disease , Genetics , Gene Regulatory Networks , Humans , Phosphorylation , Protein Processing, Post-Translational , Proteins , Metabolism , Search Engine
17.
Article in English | WPRIM | ID: wpr-772962

ABSTRACT

As a newly-identified protein post-translational modification, malonylation is involved in a variety of biological functions. Recognizing malonylation sites in substrates represents an initial but crucial step in elucidating the molecular mechanisms underlying protein malonylation. In this study, we constructed a deep learning (DL) network classifier based on long short-term memory (LSTM) with word embedding (LSTM) for the prediction of mammalian malonylation sites. LSTM performs better than traditional classifiers developed with common pre-defined feature encodings or a DL classifier based on LSTM with a one-hot vector. The performance of LSTM is sensitive to the size of the training set, but this limitation can be overcome by integration with a traditional machine learning (ML) classifier. Accordingly, an integrated approach called LEMP was developed, which includes LSTM and the random forest classifier with a novel encoding of enhanced amino acid content. LEMP performs not only better than the individual classifiers but also superior to the currently-available malonylation predictors. Additionally, it demonstrates a promising performance with a low false positive rate, which is highly useful in the prediction application. Overall, LEMP is a useful tool for easily identifying malonylation sites with high confidence. LEMP is available at http://www.bioinfogo.org/lemp.


Subject(s)
Amino Acid Sequence , Genetics , Amino Acids , Animals , Deep Learning , Forecasting , Methods , Lysine , Chemistry , Machine Learning , Malonates , Chemistry , Protein Processing, Post-Translational , Genetics
18.
Article in English | WPRIM | ID: wpr-758781

ABSTRACT

Rotavirus (RV)-infected piglets are presumed to be latent sources of heterologous RV infection in humans and other animals. In RVs, non-structural protein 4 (NSP4) is the major virulence factor with pleiotropic properties. In this study, we analyzed the nsp4 gene from porcine RVs isolated from diarrheic and non-diarrheic cases at different levels of protein folding to explore correlations to diarrhea-inducing capabilities and evolution of nsp4 in the porcine population. Full-length nsp4 genes were amplified, cloned, sequenced, and then analyzed for antigenic epitopes, RotaC classification, homology, genetic relationship, modeling of NSP4 protein, and prediction of post-translational modification. RV presence was observed in both diarrheic and non-diarrheic piglets. All nsp4 genes possessed the E1 genotype. Comparison of primary, secondary, and tertiary structure and the prediction of post-translational modifications of NSP4 from diarrheic and non-diarrheic piglets revealed no apparent differences. Sequence analysis indicated that nsp4 genes have a multi-phyletic evolutionary origin and exhibit species independent genetic diversity. The results emphasize the evolution of the E9 nsp4 genotype from the E1 genotype and suggest that the diarrhea-inducing capability of porcine RVs may not be exclusively linked to its enterotoxin gene.


Subject(s)
Animals , Classification , Clone Cells , Enterotoxins , Epitopes , Genetic Variation , Genotype , Humans , Protein Folding , Protein Processing, Post-Translational , Rotavirus , Sequence Analysis , Viral Nonstructural Proteins , Virulence
19.
Article in Chinese | WPRIM | ID: wpr-776687

ABSTRACT

OBJECTIVE@#To study the interactive regulatory effect of histone acetylation and methylation on cardiomyogenesis, and to provide a theoretical basis for the prevention and treatment of congenital heart disease.@*METHODS@#A total of 24 Kunming mice were randomly divided into embryo day 14.5 (ED 14.5) group, embryo day 16.5 (ED 16.5) group, postnatal day 0.5 (PND 0.5) group, and postnatal day 7 (PND 7) group, with 6 mice in each group, and the heart tissue of fetal and neonatal mice was collected. Colorimetry was used to measure the activities of histone acetylases (HATs) and histone methyltransferases (HMTs) in the myocardium. Western blot was used to measure the expression of H3K9ac and H3K9me3 in the myocardium.@*RESULTS@#Colorimetry showed that the activities of HATs and HMTs were higher before birth and were lower after birth. There was a significant difference in the activity of HATs in the myocardium between the PND 0.5 and PND 7 groups and the ED 14.5 group (P<0.05), as well as between the PND 7 group and the ED 16.5 group (P<0.05). There was also a significant difference in the activity of HMTs in the myocardium between the PND 7 group and the ED 14.5 and ED 16.5 groups (P<0.05). Western blot showed higher expression of H3K9ac and H3K9me3 before birth and lower expression of H3K9ac and H3K9me3 after birth, and there were significant differences in the expression H3K9ac and H3K9me3 in the myocardium between the PND 0.5 and PND 7 groups and the ED 14.5 and ED 16.5 groups (P<0.05).@*CONCLUSIONS@#The dynamic expression of HATs, HMTs, H3K9ac, and H3K9me3 is observed during cardiomyogenesis, suggesting that histone H3K9ac acetylation and histone H3K9me3 methylation mediated by HATs and HMTs may play a role in interactive regulation during cardiomyogenesis.


Subject(s)
Acetylation , Animals , Histone Acetyltransferases , Histones , Metabolism , Methylation , Mice , Protein Processing, Post-Translational
20.
Article in English | WPRIM | ID: wpr-727863

ABSTRACT

Neddylation is a post-translational protein modification process. MLN4924 is a newly discovered pharmaceutical neddylation inhibitor that suppresses cancer growth with several cancer types. In our study, we first investigated the effect of MLN4924 on colon cancer cells (HCT116 and HT29). MLN4924 significantly inhibited the neddylation of cullin-1 and colon cancer cell growth in a time and dose-dependent manner. MLN4924 induced G2/M cell cycle arrest and apoptosis in HCT116 and HT29 cells. Moreover, MLN4924 also triggered autophagy in HCT116 and HT29 cells via suppressing the PI3K/AKT/mTOR pathway. Inhibiting autophagy by autophagy inhibitor 3-MA or ATG5 knockdown reversed the function of MLN4924 in suppressing colon cancer cell growth and cell death. Interestingly, MLN4924 suppresses colon cell growth in a xenograft model. Together, our finding revealed that blocking neddylation is an attractive colon cancer therapy strategy, and autophagy might act as a novel anti-cancer mechanism for the treatment of colon cancer by MLN4924.


Subject(s)
Apoptosis , Autophagy , Cell Cycle Checkpoints , Cell Death , Colon , Colonic Neoplasms , Heterografts , HT29 Cells , Humans , Protein Processing, Post-Translational
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