scholarly journals Histone N-terminal acetyltransferase NAA40 links one-carbon metabolism to chemoresistance

Oncogene ◽  
2021 ◽  
Author(s):  
Christina Demetriadou ◽  
Anastasia Raoukka ◽  
Evelina Charidemou ◽  
Constantine Mylonas ◽  
Christina Michael ◽  
...  
Keyword(s):  
Nuclear Periphery ◽  
Metabolic Genes ◽  
Epigenetic Modifiers ◽  
Regulatory Link ◽  
Cancer Types ◽  
Xenograft Models ◽  
One Carbon Metabolism ◽  
The One

AbstractAberrant function of epigenetic modifiers plays an important role not only in the progression of cancer but also the development of drug resistance. N-alpha-acetyltransferase 40 (NAA40) is a highly specific epigenetic enzyme catalyzing the transfer of an acetyl moiety at the N-terminal end of histones H4 and H2A. Recent studies have illustrated the essential oncogenic role of NAA40 in various cancer types but its role in chemoresistance remains unclear. Here, using transcriptomic followed by metabolomic analysis in colorectal cancer (CRC) cells, we demonstrate that NAA40 controls key one-carbon metabolic genes and corresponding metabolites. In particular, through its acetyltransferase activity NAA40 regulates the methionine cycle thereby affecting global histone methylation and CRC cell survival. Importantly, NAA40-mediated metabolic rewiring promotes resistance of CRC cells to antimetabolite chemotherapy in vitro and in xenograft models. Specifically, NAA40 stimulates transcription of the one-carbon metabolic gene thymidylate synthase (TYMS), whose product is targeted by 5-fluorouracil (5-FU) and accordingly in primary CRC tumours NAA40 expression associates with TYMS levels and poorer 5-FU response. Mechanistically, NAA40 activates TYMS by preventing enrichment of repressive H2A/H4S1ph at the nuclear periphery. Overall, these findings define a novel regulatory link between epigenetics and cellular metabolism mediated by NAA40, which is harnessed by cancer cells to evade chemotherapy.

The acute transient polymorphic psychosis: a biochemical subtype of the cycloid psychosis

2003 ◽  
Vol 15 (1) ◽  
pp. 38-43 ◽  
Author(s):  
L Pepplinkhuizen ◽  
F M M A van der Heijden ◽  
S Tuinier ◽  
W M A Verhoeven ◽  
D Fekkes
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Psychotic Disorders ◽  
Acid Metabolism ◽  
Plasma Concentrations ◽  
One Carbon Metabolism ◽  
The One

Background:The pathogenesis of atypical psychoses, in particularly those characterized by polymorphic psychopathology, is hypothesized to be related to disturbances in amino acid metabolism.Objective:In the present study, the role of the amino acid serine was investigated in patients with acute transient polymorphic psychosis.Methods:Patients were loaded with serine and with the amino acids glycine and alanine as controls and subsequently evaluated for the development of psychopathological symptoms. In addition, plasma levels of amino acids were measured.Results:In a subgroup of patients suffering from atypical psychoses, this biochemical challenge resulted in the reappearance of psychedelic symptoms in particular. Furthermore, significantly lower plasma concentrations of serine were found. In vitro experiments revealed a disturbance in the one-carbon metabolism. In another group of patients the loading provoked vegetative symptoms and fatigue.Conclusions:Disturbances in amino acid metabolism may be involved in the emergence of certain psychotic disorders.

EXTH-55. TARGETING RECURRENT IDH MUTANT GLIOMA WITH CDK4/6 INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi175-vi175
Author(s):  
Julie Miller ◽  
Daniel Cahill ◽  
Lisa Melamed ◽  
Hiroaki Nagashima
Keyword(s):  
Gene Deletion ◽  
Homozygous Deletion ◽  
Therapeutic Strategies ◽  
Enhanced Sensitivity ◽  
Rb Pathway ◽  
Cancer Types ◽  
Xenograft Models ◽  
The Relationship ◽  
Inhibitor Treatment

Abstract Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.

scholarly journals BCAT1 Activates PI3K/AKT/mTOR Pathway and Contributes to the Angiogenesis and Tumorigenicity of Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiong Shu ◽  
Pan-Pan Zhan ◽  
Li-Xin Sun ◽  
Long Yu ◽  
Jun Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Western Blotting ◽  
Mtor Pathway ◽  
Clinical Samples ◽  
Xenograft Models ◽  
Cell Phenotypes

BackgroundFocusing on antiangiogenesis may provide promising choices for treatment of gastric cancer (GC). This study aimed to investigate the mechanistic role of BCAT1 in the pathogenesis of GC, particularly in angiogenesis.MethodsBioinformatics and clinical samples analysis were used to investigate the expression and potential mechanism of BCAT1 in GC. BGC823 cells with BCAT1 overexpression or silencing were induced by lentiviral transduction. Cell phenotypes and angiogenesis were evaluated. The relevant proteins were quantized by Western blotting, immunohistochemistry, or immunofluorescence. Xenograft models were constructed to confirm the role of BCAT1 in vivo.ResultsBCAT1 was overexpressed in GC patients and associated with lower survival. BCAT1 expression was correlated with proliferation-, invasion-, or angiogenesis-related markers expression and pathways. Silencing BCAT1 expression suppressed cell viability, colony formation, cycle progression, invasion, and angiogenesis of BGC823 cells, as well as the tumor growth of xenograft models, whereas overexpressing BCAT1 had the opposite results both in vitro and in vivo. Bioinformatics analysis and Western blotting demonstrated that BCAT1 activated the PI3K/AKT/mTOR pathway. The addition of LY294002 reversed the tumor growth induced by BCAT1 overexpression, further verifying this mechanism.ConclusionBCAT1 might act as an oncogene by facilitating proliferation, invasion, and angiogenesis through activation of the PI3K/AKT/mTOR pathway. This finding could aid the optimization of antiangiogenesis strategies.

ROLE OF PROTEOLYSIS AT ARGININE-275 OF TISSUE PLASMINOGEN ACTIVATOR (t-PA) AS ASSESSED BY SITE-DIRECTED MUTAGENESIS

1987 ◽  
Author(s):  
G A Vehar ◽  
K M Tate ◽  
D L Higgins ◽  
W E Holmes ◽  
H L Heyneker
Keyword(s):  
Cho Cells ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Wild Type ◽  
Single Chain ◽  
Serine Protease Family ◽  
The One ◽  
Chain Form

The significance of the cleavage at arginine-275 of human t-PA has been the subject of debate. It has been reported, as expected for a member of the serine protease family, that the single chain form is a zymogen and that generation of catalytic activity is dependent upon cleavage at arginine-275. Other groups, in contrast, have found considerable enzyme activity associated with the one-chain form of t-PA. To clarify the functional significance of this proteolysis and circumvent cleavage of one-chain t-PA by itself or plasmin, site-directed mutagenesis was employed to change the codon of arginine-275 to specify a glutamic acid. The resulting plasmid was used to transfect CHO cells. The single chain mutant [Glu-275 t-PA] was expressed in CHO cells and the protein purified by conventional techniques. The mutant enzyme could be converted to the two-chain form by V8 protease, but not by plasmin. Glu-275 t-PA was 8 times less active in the cleavage of a tripeptide substrate and 20-50 times less active in the activation of plasminogen in the absence of firbrin(ogen) than its two-chain form. In the presence of fibrin(ogen), in contrast, the one and two-chain forms of Glu-275 t-PA were equal in their ability to activate plasminogen in the presence of fibrin(ogen). The activity in these assays was equal to the activity of wild type t-PA. In addition, it was observed that fibrin bound considerably more of the one-chain form of t-PA than the two chain forms of t-PA and the Glu-275 mutant. The one and two-chain forms of the wild type and mutated t-PA were found to slowly form complexes with plasma protease inhibitors in vitro, although the one-chain forms were less reactive with alpha-2-macroglobulin. It can be concluded that the one-chain form of t-PA appears to be fully functional under physiologic conditions and has an increased affinity for fibrin compared to two-chain t-PA.

Platelet Models and Their Possible Usefulness in the Study of Migraine Pathogenesis

Cephalalgia ◽  
1995 ◽  
Vol 15 (4) ◽  
pp. 265-271 ◽  
Author(s):  
G D'Andrea ◽  
AR Cananzi ◽  
F Perini ◽  
L Hasselmark
Keyword(s):  
Primary Headache ◽  
The Other ◽  
Clinical Aspects ◽  
Metabolic Characteristics ◽  
Dense Bodies ◽  
Migraine Pathogenesis ◽  
Serotonin Turnover ◽  
The One

Platelets may be linked to migraine. On the one hand they are activated during the migraine attack and thus may participate in the pathogenesis of the disorder (the nature of this activation is still unknown). In order to understand this platelet anomaly, we discuss the data available in the literature. In particular, we review recent in vitro studies of a-granules and dense bodies secretion, and aggregation induced by collagen and PAF. On the other hand, platelets share many metabolic characteristics with serotonergic neurons and endothelial cells. Accordingly, platelets have been used to investigate the possible role of serotonin turnover and nitric oxide function in migraine. In both cases, the data obtained have shown peculiar abnormalities that may explain pathogenetic and clinical aspects of primary headache.

scholarly journals Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone

2021 ◽  
Vol 12 ◽  
Author(s):  
Shashank Kumar ◽  
Kumari Sunita Prajapati ◽  
Mohd Shuaib ◽  
Prem Prakash Kushwaha ◽  
Hardeep Singh Tuli ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Xenograft Models ◽  
Inhibitory Potential ◽  
Pharmacological Potential

In the present article we present an update on the role of chemoprevention and other pharmacological activities reported on kurarinone, a natural flavanone (from 1970 to 2021). To the best of our knowledge this is the first and exhaustive review of kurarinone. The literature was obtained from different search engine platforms including PubMed. Kurarinone possesses anticancer potential against cervical, lung (non-small and small), hepatic, esophageal, breast, gastric, cervical, and prostate cancer cells. In vivo anticancer potential of kurarinone has been extensively studied in lungs (non-small and small) using experimental xenograft models. In in vitro anticancer studies, kurarinone showed IC50 in the range of 2–62 µM while in vivo efficacy was studied in the range of 20–500 mg/kg body weight of the experimental organism. The phytochemical showed higher selectivity toward cancer cells in comparison to respective normal cells. kurarinone inhibits cell cycle progression in G2/M and Sub-G1 phase in a cancer-specific context. It induces apoptosis in cancer cells by modulating molecular players involved in apoptosis/anti-apoptotic processes such as NF-κB, caspase 3/8/9/12, Bcl2, Bcl-XL, etc. The phytochemical inhibits metastasis in cancer cells by modulating the protein expression of Vimentin, N-cadherin, E-cadherin, MMP2, MMP3, and MMP9. It produces a cytostatic effect by modulating p21, p27, Cyclin D1, and Cyclin A proteins in cancer cells. Kurarinone possesses stress-mediated anticancer activity and modulates STAT3 and Akt pathways. Besides, the literature showed that kurarinone possesses anti-inflammatory, anti-drug resistance, anti-microbial (fungal, yeast, bacteria, and Coronavirus), channel and transporter modulation, neuroprotection, and estrogenic activities as well as tyrosinase/diacylglycerol acyltransferase/glucosidase/aldose reductase/human carboxylesterases 2 inhibitory potential. Kurarinone also showed therapeutic potential in the clinical study. Further, we also discussed the isolation, bioavailability, metabolism, and toxicity of Kurarinone in experimental models.

scholarly journals An important role of the interplay between Bdnf transcription and histone acetylation in epileptogenesis

2020 ◽  
Author(s):  
Agnieszka Walczak ◽  
Iwona Czaban ◽  
Anna Skupien ◽  
Katarzyna K. Pels ◽  
Andrzej A. Szczepankiewicz ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Gene Transcription ◽  
Histone Deacetylases ◽  
Mossy Fiber ◽  
Trichostatin A ◽  
Nuclear Periphery ◽  
Neuronal Activation ◽  
Neuronal Excitation

AbstractBrain-Derived Neurotrophic Factor is one of the most important trophic proteins in the brain. The role of this growth factor in neuronal plasticity, in health and disease, has been extensively studied. However, mechanisms of epigenetic regulation of Bdnf gene expression in epilepsy are still elusive. In our previous work, using a rat model of neuronal activation upon kainate-induced seizures, we observed a repositioning of Bdnf alleles from the nuclear periphery towards the nuclear center. This change of Bdnf intranuclear position was associated with transcriptional gene activity.In the present study, using the same neuronal activation model, we analyzed the relation between the percentage of the Bdnf allele at the nuclear periphery and clinical and morphological traits of epilepsy. We observed that the decrease of the percentage of the Bdnf allele at the nuclear periphery correlates with stronger mossy fiber sprouting - an aberrant form of excitatory circuits formation. Moreover, using in vitro hippocampal cultures we showed that Bdnf repositioning is a consequence of the transcriptional activity. Inhibition of RNA polymerase II activity in primary cultured neurons with Actinomycin D completely blocked Bdnf gene transcription and repositioning observed after neuronal excitation. Interestingly, we observed that histone deacetylases inhibition with Trichostatin A induced a slight increase of Bdnf gene transcription and its repositioning even in the absence of neuronal excitation. Presented results provide novel insight into the role of BDNF in epileptogenesis. Moreover, they strengthen the statement that this particular gene is a good candidate to search for a new generation of antiepileptic therapies.

scholarly journals SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism

Science ◽  
2018 ◽  
Vol 362 (6416) ◽  
pp. eaat9528 ◽  
Author(s):  
Nora Kory ◽  
Gregory A. Wyant ◽  
Gyan Prakash ◽  
Jelmi uit de Bos ◽  
Francesca Bottanelli ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Mitochondrial Membrane ◽  
Mitochondrial Pathway ◽  
Genetic Screen ◽  
Inner Mitochondrial Membrane ◽  
Unknown Mechanism ◽  
One Carbon Metabolism ◽  
The One ◽  
Mitochondrial Membrane Protein

One-carbon metabolism generates the one-carbon units required to synthesize many critical metabolites, including nucleotides. The pathway has cytosolic and mitochondrial branches, and a key step is the entry, through an unknown mechanism, of serine into mitochondria, where it is converted into glycine and formate. In a CRISPR-based genetic screen in human cells for genes of the mitochondrial pathway, we found sideroflexin 1 (SFXN1), a multipass inner mitochondrial membrane protein of unclear function. Like cells missing mitochondrial components of one-carbon metabolism, those null for SFXN1 are defective in glycine and purine synthesis. Cells lacking SFXN1 and one of its four homologs, SFXN3, have more severe defects, including being auxotrophic for glycine. Purified SFXN1 transports serine in vitro. Thus, SFXN1 functions as a mitochondrial serine transporter in one-carbon metabolism.

scholarly journals Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv1-iv2
Author(s):  
Thomas Oliver Millner ◽  
Barbara Ricci ◽  
Xinyu Zhang ◽  
Nicola Pomella ◽  
Silvia Marino
Keyword(s):  
Mouse Model ◽  
Genome Wide ◽  
Human Primary Cells ◽  
Epigenetic Regulator ◽  
Xenograft Models ◽  
Human Gbm ◽  
And Migration ◽  
Proliferation And Migration

Abstract Introduction The epigenetic regulator Bmi1 is essential for the self-renewal of neural stem cells (NSC), and highly expressed in glioblastoma (GBM) stem/initiating cells (GIC), where knockdown significantly reduces tumour growth in xenograft models. We have used a combined genome-wide and target gene-driven approach to identify EphrinA5 (EfnA5) as a mediator of Bmi1 function in mouse and human GIC. Methods and results We compared mGIC, from a PTEN/p53 deletion mouse model, to matched NSC. Combined ChIPSeq and RNASeq showed a differential redistribution of the repressive PRC mark H3K27me3 in mGIC, and that transcriptional regulation is Bmi1-dependent in a proportion of H3K27me3 marked genes. Subsequently, using shRNA knockdown, we show that Bmi1 regulates cell morphology, proliferation and migration/invasion via repression of EfnA5 in mGIC, and that the same mechanism is essential for GBM development in an allograft model. To confirm the translational potential of the BMI1/EFNA5 pathway we examined published RNA microarray, RNAseq and single-cell RNAseq datasets and found a significant inverse relationship between BMI1 and EFNA5. Finally, we show that BMI1 also regulates cell proliferation via repression of EFNA5 in primary human GIC in vitro. Conclusions We present evidence from a mouse model, human expression datasets and human primary cells showing that the Bmi1-EfnA5 pathway plays a prominent regulatory role in GIC. As the anti-proliferative role of BMI1 silencing is mediated by de-repression of EFNA5 in hGIC, precision targeting of Ephrin signalling, for example with agents that mimic EFNA5 action, could be an effective therapeutic tool in human GBM overexpressing BMI1.

EBAG9 is a tumor‐promoting and prognostic factor for bladder cancer.

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Bladder Cancer ◽  
Immunohistochemical Study ◽  
Tumor Formation ◽  
Loss Of Function ◽  
Xenograft Models ◽  
Prostate Cancers ◽  
And Migration

Upregulation of EBAG9 expression has been observed in severalmalignant tumors such as advanced breast and prostate cancers,indicating that EBAG9 may contribute to tumor proliferation. Inthe present study, we assess the role of EBAG9 in bladder cancer.We generated human bladder cancer EJ cells stably expressingFLAG-tagged EBAG9 (EJ-EBAG9) or empty vector (EJ-vector),and investigated whether EBAG9 overexpression modulates cellgrowth and migration in vitro as well as the in vivo tumor formationof EJ transfectants in xenograft models of BALB/c nude mice.EBAG9 overexpression promoted EJ cell migration, while theeffect of EBAG9 to cultured cell growth was rather minimal.Tumorigenic experiments in nude mice showed that the size of EJEBAG9-derived tumors was significantly larger than EJ-vectorderivedtumors. Loss-of-function study for EBAG9 using smallinterfering RNA (siRNA) in xenografts with parental EJ cellsshowed that the intra-tumoral injection of EBAG9 siRNA markedlyreduced the EJ tumor formation compared with controlsiRNA. Furthermore, immunohistochemical study for EBAG9expression was performed in 60 pathological bladder cancer specimens.Intense and diffuse cytoplasmic immunostaining wasobserved in 45% of the bladder cancer cases. Positive EBAG9immunoreactivity was closely correlated with poor prognosis ofthe patients (p 5 0.0001) and it was an independent prognosticpredictor for disease-specific survival in multivariate analysis(p 5 0.003). Our results indicate that EBAG9 would be a crucialregulator of tumor progression and a potential prognostic markerfor bladder cancer.

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