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Overexpression of ASS1 inhibited cell proliferation, migration and invasion. A. Transfected U87 and U251 cells with ASS1 overexpression plasmid or shRNA, and the interference efficiency was detected by qRT-PCR. B. Transfected U87 and U251 cells with ASS1 overexpression plasmid or shRNA, and the interference efficiency was detected by Western blot. C. Proliferation ability of glioma cells transfected with ASS1 overexpression plasmid or sh-ASS1 was detected by EdU experiment. (magnification: 200X) D-E. Effect of ASS1 on cell migration and invasion were detected by transwell migration and invasion assay. (magnification: 200X) *p < 0.05; **p < 0.01.
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Statement of Retraction
The Publisher of the journal Bioengineered, have retracted the following article:
Miao YQ, Chen W, Zhou J, Shen Q, Sun Y, Li T, Wang SC. N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner. Bioengineered. 2022 Jan;13(1):1858-1871....
Contexts in source publication
Context 1
... explore the biological effects of ASS1 in glioma, we chose U87 and U251 cells for the experiments. First, we increased or decreased the expression levels of ASS1 in glioma cells using an overexpression plasmid or shRNA and verified the transfection efficiency by qRT-PCR and Western blotting assays (Figure 2a, b). Through EdU and transwell assays, we found that overexpression of ASS1 inhibited the cell proliferation, migration, and invasion, while that of sh-ASS1 significantly promoted the growth, invasion, and metastasis of U87 and U251 cells (Figure 2c-e). ...
Context 2
... we increased or decreased the expression levels of ASS1 in glioma cells using an overexpression plasmid or shRNA and verified the transfection efficiency by qRT-PCR and Western blotting assays (Figure 2a, b). Through EdU and transwell assays, we found that overexpression of ASS1 inhibited the cell proliferation, migration, and invasion, while that of sh-ASS1 significantly promoted the growth, invasion, and metastasis of U87 and U251 cells (Figure 2c-e). ...
Citations
... GBM is often associated with high levels of expression of both m 6 A methyltransferase-related proteins, METTL3 and WTAP, and ALKBH5 (Fig. 3g), while higher glioma grades and poorer clinical outcomes are found to be correlated with decreased FTO expression and increased expression of YTHDF2 and YTHDF3 [174][175][176][177][178][179]. Functionally, knockdown of METTL3, METTL14, YTHDC1 and FTO, or overexpression of METTL14, WTAP, YTHDF1 and IGF2BP3 promotes glioma stem cell (GSC) proliferation, selfrenewal, and tumorigenesis; on the contrary, overexpression of METTL3 and FTO, silencing ALKBH5, WTAP, METTL3, YTHDF1, YTHDF2 and IFG2BP3, or treatment with FTO inhibitors (including MA2, R-2HG, and FTO-04) inhibits proliferation and self-renewal of GSCs and GSC-induced tumorigenesis [174,175,[178][179][180][181][182][183][184][185][186][187]. The variable effects of manipulating different m 6 A regulators on GSC proliferation and tumorigenesis in different studies probably reflects different cancer cell lines examined. ...
Various chemical modifications of all RNA transcripts, or epitranscriptomics, have emerged as crucial regulators of RNA metabolism, attracting significant interest from both basic and clinical researchers due to their diverse functions in biological processes and immense clinical potential as highlighted by the recent profound success of RNA modifications in improving COVID-19 mRNA vaccines. Rapid accumulation of evidence underscores the critical involvement of various RNA modifications in governing normal neural development and brain functions as well as pathogenesis of brain disorders. Here we provide an overview of RNA modifications and recent advancements in epitranscriptomic studies utilizing animal models to elucidate important roles of RNA modifications in regulating mammalian neurogenesis, gliogenesis, synaptic formation, and brain function. Moreover, we emphasize the pivotal involvement of RNA modifications and their regulators in the pathogenesis of various human brain disorders, encompassing neurodevelopmental disorders, brain tumors, psychiatric and neurodegenerative disorders. Furthermore, we discuss potential translational opportunities afforded by RNA modifications in combatting brain disorders, including their use as biomarkers, in the development of drugs or gene therapies targeting epitranscriptomic pathways, and in applications for mRNA-based vaccines and therapies. We also address current limitations and challenges hindering the widespread clinical application of epitranscriptomic research, along with the improvements necessary for future progress.
... Sci. 2023,24, 10668 ...
Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis-all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal.
... An increasing number of studies have focused on the role of RNA m 6 A methylation in the development of various neurological diseases, such as Parkinson's disease [23], Alzheimer's disease [24,25], multiple sclerosis [26], tumours [27][28][29], epilepsy [30], and neuropsychiatric disorders [31]. However, to date, there is limited research focusing on the role of RNA m 6 A methylation in TBI and BGA. ...
The brain-gut axis (BGA) is a significant bidirectional communication pathway between the brain and gut. Traumatic brain injury (TBI) induced neurotoxicity and neuroinflammation can affect gut functions through BGA. N6-methyladenosine (m6A), as the most popular posttranscriptional modification of eukaryotic mRNA, has recently been identified as playing important roles in both the brain and gut. However, whether m6A RNA methylation modification is involved in TBI-induced BGA dysfunction is not clear. Here, we showed that YTHDF1 knockout reduced histopathological lesions and decreased the levels of apoptosis, inflammation, and oedema proteins in brain and gut tissues in mice after TBI. We also found that YTHDF1 knockout improved fungal mycobiome abundance and probiotic (particularly Akkermansia) colonization in mice at 3 days post-CCI. Then, we identified the differentially expressed genes (DEGs) in the cortex between YTHDF1-knockout and WT mice. These genes were primarily enriched in the regulation of neurotransmitter-related neuronal signalling pathways, inflammatory signalling pathways, and apoptotic signalling pathways. This study reveals that the ITGA6-mediated cell adhesion molecule signalling pathway may be the key feature of m6A regulation in TBI-induced BGA dysfunction. Our results suggest that YTHDF1 knockout could attenuate TBI-induced BGA dysfunction.
... Other studies corroborated the association between high METTL3 expression and reduced glioma proliferation; however, METTL3 silencing was shown to suppress vasculogenic mimicry, important for tumour angiogenesis [95,96]. Meanwhile, overexpression of another m 6 A writer, METTL4, was shown to promote glioma cell proliferation and migration [95,97]. Recently, FTO knockdown or inhibition was shown to suppress GBM proliferation via an m 6 A-dependent depletion of MYC levels [98]. ...
... Notably, YTHDF1 knockdown increased the sensitivity of glioma cells to the antiproliferative effects of TMZ, demonstrating its potential as a synergistic target for improved treatment response in GBM. Another YTH family member, YTHDF2, is also a potential target for glioma treatment, with studies linking YTHDF2 expression to glioma progression [97,109]. Increased in GSCs, YTHDF2 plays a vital role in stem maintenance, and it enhances tumour growth in mice through stabilising MYC (YTHDF2-MYC) and targeting IGFBP3. ...
Simple Summary
Glioblastoma is a complex and aggressive primary brain tumour that is rapidly fatal. Timely and accurate diagnosis is therefore crucial. Here, we explore the newly emerging field of epitranscriptomics to understand the modifications that occur on RNA molecules in the healthy and diseased brain, focusing on glioblastoma. RNA modifications are modulated by various regulators and are diverse, specific, reversible, and involved in many aspects of brain tumour biology. Epitranscriptomic biomarkers may therefore be ideal candidates for clinical diagnostic workflows. This review summarises the current understanding of epitranscriptomics and its clinical relevance in brain cancer diagnostics.
Abstract
RNA modifications are diverse, dynamic, and reversible transcript alterations rapidly gaining attention due to their newly defined RNA regulatory roles in cellular pathways and pathogenic mechanisms. The exciting emerging field of ‘epitranscriptomics’ is predominantly centred on studying the most abundant mRNA modification, N6-methyladenine (m⁶A). The m⁶A mark, similar to many other RNA modifications, is strictly regulated by so-called ‘writer’, ‘reader’, and ‘eraser’ protein species. The abundance of genes coding for the expression of these regulator proteins and m⁶A levels shows great potential as diagnostic and predictive tools across several cancer fields. This review explores our current understanding of RNA modifications in glioma biology and the potential of epitranscriptomics to develop new diagnostic and predictive classification tools that can stratify these highly complex and heterogeneous brain tumours.
... As the most abundant modification in eukaryotic mRNA and lncRNA, m 6 A has been reported to play a key role in regulating mRNA transcript, splicing, transportation, translation and degradation during physiological and pathological progression (Golan-Gerstl et al. 2011;Yu et al. 2018;Zheng et al. 2013). There is evidence showing that m 6 A contributes to the malignant biological behavior of gliomas, for instance, growth, proliferation and metastasis (Jin et al. 2012;Miao et al. 2022). Since m 6 A is regulated by the "writer", "eraser", and "reader", the studies related to m 6 A are mainly focused on these regulators to reveal biological functions of m 6 A indirectly. ...
... A study revealed that arginine-succinate synthase 1 (ASS1) is downregulated in gliomas, inhibiting the proliferation, metastasis, and growth of glioma cells. In machinery, m 6 A is induced in ASS1 mRNA by METTL14 and recognized by YTHDF2 which renders the degradation of ASS1, and consequently suppresses the expression of ASS1 in gliomas (Miao et al. 2022). Another study performed a similar model: m 6 A induced by METTL3 is recognized by YTHDF2 to facilitate the degradation of UBXN1, which activates the oncogenic NF-κB signal and promotes the proliferation and migration of glioma cells (Chai et al. 2021). ...
Gliomas are the most common central cancer with high aggressive-capacity and poor prognosis, remaining to be the threat of most patients. With the blood–brain barrier and highly malignant progression, the efficacy of high-intensity treatment is limited. The N6-methyladenine (m⁶A) modification is found in rRNA, snRNA, miRNA, lncRNA, and mRNA, influencing the metabolism and translation of these RNAs and consequently regulating the proliferation, metastasis, apoptosis, etc. of glioma cells. The key role that m⁶A modification in gliomas has played makes it a prospective target for diagnosis and treatment. However, with studying deeper in m⁶A modification and gliomas, the conclusion and mechanism are abundant and complex. This review focused on the dysregulation of m⁶A regulators and m⁶A modification of key genes and pathways in Hallmarks of gliomas. Furthermore, the potential of exploiting m⁶A modification for gliomas diagnosis and therapeutics was also discussed. This review will summarize the recent studies about m⁶A modification, revealing that m⁶A modification plays an important role in the malignant progression, angiogenesis, microenvironment, and genome instability in gliomas by exploring the interaction and network between m⁶A modification-related regulators and classical tumor-related genes. And it might provide some clue for the molecular mechanism, diagnosis, and treatment of gliomas.
Graphical Abstract
... It was shown earlier that METTL3-mediated m6A RNA modification is critical for glioblastoma stem cell maintenance and dedifferentiation of glioma cells [18]. The overexpression of METTL14 also leads to decreasing ASS1 expression, promoting cell proliferation, migration, and invasion in glioma [102]. At the same time, the knockdown of METTL3 and METTL14 dramatically promotes human glioblastoma stem cell growth, self-renewal, and tumorigenesis [21]. ...
This review is devoted to changes in the post-transcriptional maturation of RNA in human glioblastoma cells, which leads to disruption of the normal course of apoptosis in them. The review thoroughly highlights the latest information on both post-transcriptional modifications of certain regulatory RNAs, associated with the process of apoptosis, presents data on the features of apoptosis in glioblastoma cells, and shows the relationship between regulatory RNAs and the apoptosis in tumor cells. In conclusion, potential target candidates are presented that are necessary for the development of new drugs for the treatment of glioblastoma.
... Alteration of m 6 A modification exerts significant effects on brain tissue development, learning and memory ability, stem cell renewal and differentiation, synaptic regeneration, and other biological functions (Figure 7). Therefore, the abnormal expression of m 6 A-related proteins may lead to the development of various neurological diseases, such as PD [145][146][147], AD [148][149][150][151][152], MS [153], tumours [154][155][156], epilepsy [157], and neuropsychiatric disorders [158]. TBI, as one of the major diseases of CNS, often causes memory problems in humans [159]. ...
... Gut microbial metabolites and fermentation products, such as short-chain fatty acids (SCFAs), tryptophan metabolites, sphingolipids, and polyamines, have been known to partially regulate the effect of the gut microbiome on the host by modulating transcription and epigenetic modifications [169][170][171][172]. Sabrina Jabs et al. found that m 6 A modification spectra in both the mouse ceca and liver were affected by the presence of the gut microbiome by MERIP-Seq [27]. Xiaoyun Wang et al. carried out mass spectrometry and m 6 A sequencing on GF and SPF Therefore, the abnormal expression of m 6 A-related proteins may lead to the development of various neurological diseases, such as PD [145][146][147], AD [148][149][150][151][152], MS [153], tumours [154][155][156], epilepsy [157], and neuropsychiatric disorders [158]. TBI, as one of the major diseases of CNS, often causes memory problems in humans [159]. ...
The brain–gut axis (BGA) is an important bidirectional communication pathway for the development, progress and interaction of many diseases between the brain and gut, but the mechanisms remain unclear, especially the post-transcriptional regulation of BGA after traumatic brain injury (TBI). RNA methylation is one of the most important modifications in post-transcriptional regulation. N6-methyladenosine (m6A), as the most abundant post-transcriptional modification of mRNA in eukaryotes, has recently been identified and characterized in both the brain and gut. The purpose of this review is to describe the pathophysiological changes in BGA after TBI, and then investigate the post-transcriptional bidirectional regulation mechanisms of TBI-induced BGA dysfunction. Here, we mainly focus on the characteristics of m6A RNA methylation in the post-TBI BGA, highlight the possible regulatory mechanisms of m6A modification in TBI-induced BGA dysfunction, and finally discuss the outcome of considering m6A as a therapeutic target to improve the recovery of the brain and gut dysfunction caused by TBI.
... Methyltransferase 14 (METTL14), a RNA N6-adenosine methyltransferase, participates in tumor development via modulating RNA function (Chen et al., 2020). ASS1 is a target of METTL14mediated N6-methyladenosine modification (Miao et al., 2022). Specifically, METTL14 upregulation increases mRNA m6A modification of ASS1 and suppresses ASS1 transcriptional expression. ...
Metabolic reprogramming is an emerging hallmark of tumor cells. In order to survive in the nutrient-deprived environment, tumor cells rewire their metabolic phenotype to provide sufficient energy and build biomass to sustain their transformed state and promote malignant behaviors. Amino acids are the main compositions of protein, which provide key intermediate substrates for the activation of signaling pathways. Considering that cells can synthesize arginine via argininosuccinate synthase 1 (ASS1), arginine is regarded as a non-essential amino acid, making arginine depletion as a promising therapeutic strategy for ASS1-silencing tumors. In this review, we summarize the current knowledge of expression pattern of ASS1 and related signaling pathways in cancer and its potential role as a novel therapeutic target in cancer. Besides, we outline how ASS1 affects metabolic regulation and tumor progression and further discuss the role of ASS1 in arginine deprivation therapy. Finally, we review approaches to target ASS1 for cancer therapies.
... Accumulating evidence has revealed the unique role of m6A RNA methylation in the genesis and development of cancer including glioma. A series of studies using the knockdown model of METTL3 and METTL14 observed a reduction of m6A extent accompanied by upregulation of oncogenes and downregulation of tumor suppressors [20,21] . On the contrary, overexpression of METTL3 leads to decreased proliferation and migration of glioma cells. ...
N6-methyladenosine (m6A) modification is one of the most abundant RNA modification methods in the eukaryote. It was reported that abnormal expression of m6A-related genes is closely associated with the tumorigenesis and progression of glioma. However, the role of m6A RNA methylation in the development of glioma is still unclear. In the current study, we defined m6A-related clusters in glioma cohorts from The Cancer Genome Atlas (TCGA) database which exhibited distinct outcomes in OS. From differentially expressed genes between these clusters, m6A-associated prognostic genes were further narrowed down. Eventually, FRA10AC1, GPR85, MARCHF5, and NUAK2 were selected to form the m6Amethylation-based prognostic signature (MMS) of glioma by Cox and LASSO regression analysis. Subsequently, the efficacy and effectiveness of MMS were examined in the training, testing, and whole groups. Kaplan-Meier survival curve indicated high- and low-risk subgroups divided by MMS showed significantly different OS, and the AUCs of MMS reached 0.75 in all groups. In combined analysis with other clinical-pathological factors, MMS was proved as an independent predictive standard of glioma prognosis. In addition, gene enrichment revealed changes in signaling pathways, biological processes and hallmark gene sets between high- and low-risk subgroups. Last but not least, potential therapeutic molecules for the high-risk patient with MMS were subsequently explored. In general, our study provided MMS, a novel molecular panel closely associated with m6A methylation that holds high efficacy in predicting the prognosis of glioma.
... Overexpression of METTL14 markedly elevated ASS1 mRNA m 6 A modification and suppressed ASS1 mRNA expression. Moreover, the authors revealed that METTL14-mediated ASS1 mRNA degradation relied on the YTH m 6 A RNA-binding protein 2 (YTHDF2)-dependant pathway [67]. ...
Glioblastoma is the most common and most lethal primary malignant brain tumor. N6-methyladenosine (m6A) is a widespread and abundant internal messenger RNA (mRNA) modification found in eukaryotes. Accumulated evidence demonstrates that m6A modification is aberrantly activated in human cancers and is critical for tumorigenesis and metastasis. m6A modification is also strongly involved in key signaling pathways and is associated with prognosis in glioblastoma. Here, we briefly outline the functions of m6A and its regulatory proteins, including m6A writers, erasers, and readers of the fate of RNA. We also summarize the latest breakthroughs in this field, describe the underlying molecular mechanisms that contribute to the tumorigenesis and progression, and highlight the inhibitors targeting the factors in m6A modification in glioblastoma. Further studies focusing on the specific pathways of m6A modification could help identify biomarkers and therapeutic targets that might prevent and treat glioblastoma.
