Bioinform Biol Insights. 2021 Feb 3;15:1177932220988508. doi: 10.1177/1177932220988508. eCollection 2021.

ABSTRACT

Cutaneous melanoma is the most aggressive type of skin cancer which its incidence has significantly increased in recent years worldwide. Thus, more investigations are required to identify the underlying mechanisms of melanoma malignant transformation and metastasis. In this context, long noncoding RNAs (lncRNAs) are a new type of noncoding transcripts that their dysregulations are associated with almost all cancers including melanoma. However, the precise functional roles of most of the significantly altered lncRNAs in melanoma have not yet been fully inspected. In this study, a comprehensive list of lncRNAs was interrogated across cutaneous melanoma samples to identify the significantly altered/dysregulated lncRNAs. To this end, lncRNAs were filtered in several steps and the selected lncRNAs projected to a bioinformatic and systems biology analysis using several publicly available databases and tools such as GEPIA and cBioPortal. According to our results, 30 lncRNAs were notably altered/dysregulated in cutaneous melanoma most of which were co-expressed with each other. Also, co-expression/alteration and differential expression analyses led to the selection of 12 out of these 30 lncRNAs as cutaneous melanoma key lncRNAs. Furthermore, functional demonstrated that these 12 lncRNAs might be involved in melanoma-relevant biological processes and pathways. In addition, the end result of our analyses demonstrated that these lncRNAs are associated with the clinicopathological features of melanoma patients. These 12 lncRNAs need to be further investigated in future studies to characterize their exact roles in melanoma development and to identify their potential for being used as drug targets and/or biomarkers for cutaneous melanoma.

PMID:33613027 | PMC:PMC7868446 | DOI:10.1177/1177932220988508

Sens Actuators B Chem. 2021 Feb 16:129663. doi: 10.1016/j.snb.2021.129663. Online ahead of print.

ABSTRACT

The global outbreak of coronavirus disease and rapid spread of the causative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent a significant threat to human health. A key mechanism of human SARS-CoV-2 infection is initiated by the combination of human angiotensin-converting enzyme 2 (hACE2) and the receptor-binding domain (RBD) of the SARS-CoV-2-derived spike glycoprotein. Despite the importance of these protein interactions, there is still insufficient detection methods to observe their activity at the cellular level. Herein, we developed a novel fluorescence resonance energy transfer (FRET)-based hACE2 biosensor to monitor the interaction between hACE2 and SARS-CoV-2 RBD. This biosensor facilitated the visualization of hACE2-RBD activity with high spatiotemporal resolutions at the single-cell level. Further studies revealed that the FRET-based hACE2 biosensors were sensitive to both exogenous and endogenous hACE2 expression, suggesting that they might be safely applied to the early stage of SARS-CoV-2 infection without direct virus use. Therefore, our novel biosensor could potentially help develop drugs that target SARS-CoV-2 by inhibiting hACE2-RBD interaction.

PMID:33612970 | PMC:PMC7885701 | DOI:10.1016/j.snb.2021.129663

New Phytol. 2020 Dec 7. doi: 10.1111/nph.17144. Online ahead of print.

ABSTRACT

Plant roots are specialized belowground organs that spatiotemporally shape their development in function of varying soil conditions. This root plasticity relies on intricate molecular networks driven by phytohormones, such as auxin and jasmonate (JA). Loss-of-function of the NOVEL INTERACTOR OF JAZ (NINJA), a core component of the JA signaling pathway, leads to enhanced triterpene biosynthesis, in particular of the thalianol gene cluster, in Arabidopsis thaliana roots. We have investigated the biological role of thalianol and its derivatives by focusing on Thalianol Synthase (THAS) and Thalianol Acyltransferase 2 (THAA2), two thalianol cluster genes that are upregulated in the roots of ninja mutant plants. THAS and THAA2 activity was investigated in yeast, and metabolite and phenotype profiling of thas and thaa2 loss-of-function plants was carried out. THAA2 was shown to be responsible for the acetylation of thalianol and its derivatives, both in yeast and in planta. In addition, THAS and THAA2 activity was shown to modulate root development. Our results indicate that the thalianol pathway is not only controlled by phytohormonal cues, but also may modulate phytohormonal action itself, thereby affecting root development and interaction with the environment.

PMID:33616937 | DOI:10.1111/nph.17144

Biochem Soc Trans. 2021 Feb 22:BST20190955. doi: 10.1042/BST20190955. Online ahead of print.

ABSTRACT

The Polycomb system is essential for stable gene silencing in many organisms. This regulation is achieved in part through addition of the histone modifications H3K27me2/me3 by Polycomb Repressive Complex 2 (PRC2). These modifications are believed to be the causative epigenetic memory elements of PRC2-mediated silencing. As these marks are stored locally in the chromatin, PRC2-based memory is a cis-acting system. A key feature of stable epigenetic memory in cis is PRC2-mediated, self-reinforcing feedback from K27-methylated histones onto nearby histones in a read-write paradigm. However, it was not clear under what conditions such feedback can lead to stable memory, able, for example, to survive the perturbation of histone dilution at DNA replication. In this context, computational modelling has allowed a rigorous exploration of possible underlying memory mechanisms and has also greatly accelerated our understanding of switching between active and silenced states. Specifically, modelling has predicted that switching and memory at Polycomb loci is digital, with a locus being either active or inactive, rather than possessing intermediate, smoothly varying levels of activation. Here, we review recent advances in models of Polycomb control, focusing on models of epigenetic switching through nucleation and spreading of H3K27me2/me3. We also examine models that incorporate transcriptional feedback antagonism and those including bivalent chromatin states. With more quantitative experimental data on histone modification kinetics, as well as single-cell resolution data on transcription and protein levels for PRC2 targets, we anticipate an expanded need for modelling to help dissect increasingly interconnected and complex memory mechanisms.

PMID:33616630 | DOI:10.1042/BST20190955

Elife. 2021 Feb 22;10:e60220. doi: 10.7554/eLife.60220. Online ahead of print.

ABSTRACT

In previous work, we showed that intrinsically disordered regions (IDRs) of proteins contain sequence-distributed molecular features that are conserved over evolution, despite little sequence similarity that can be detected in alignments (Zarin et al. 2019). Here, we aim to use these molecular features to predict specific biological functions for individual IDRs and identify the molecular features within them that are associated with these functions. We find that the predictable functions are diverse. Examining the associated molecular features, we note some that are consistent with previous reports, and identify others that were previously unknown. We experimentally confirm that elevated isoelectric point and hydrophobicity, features that are positively associated with mitochondrial localization, are necessary for mitochondrial targeting function. Remarkably, increasing isoelectric point in a synthetic IDR restores weak mitochondrial targeting. We believe feature analysis represents a new systematic approach to understand how biological functions of IDRs are specified by their protein sequences.

PMID:33616531 | DOI:10.7554/eLife.60220

Int J Syst Evol Microbiol. 2021 Feb 22. doi: 10.1099/ijsem.0.004663. Online ahead of print.

ABSTRACT

Members of the genus Sneathia are fastidious bacteria that predominantly colonise the female genital tract and are significantly associated with reproductive disorders and genital and neonatal disease. From a taxonomical perspective, the genus only comprises the species Sneathia sanguinegens. Numerous reports on a second species, 'Sneathia amnii', have been published, but the name has never been validated. The same is the case for 'Leptotrichia amnionii', which was previously shown to belong to the same species as 'Sneathia amnii'. We studied strains DSM 16631T and DSM 16630, which have been identified and deposited as 'Leptotrichia amnionii' previously. At the time of isolation, these strains were found to be most closely related to, but clearly different from, Sneathia sanguinegens based on 16S rRNA gene sequence similarities. Both strains proved to be almost indistinguishable from 'Sneathia amnii' based on molecular, morphological and physiological traits. The 16S rRNA gene sequence analysis revealed that strain DSM 16631T was assigned to the genus Sneathia with a sequence similarity of 95.47 % to Sneathia sanguinegens CCUG 41628T, followed by type strains of Caviibacter abscessus (93.03 %), Oceanivirga salmonicida (92.68 %) and Oceanivirga miroungae (91.97 %) as the next closely related members of the Leptotrichiaceae. The novel species was also clearly differentiated from other related taxa by core genome phylogeny, average nucleotide and amino acid identities, in silico DNA-DNA hybridization and MALDI-TOF MS. With respect to chemotaxonomic and physiological patterns, strains DSM 16631T and DSM 16630 were again highly similar to Sneathia sanguinegens. On the basis of these data, we propose the novel species Sneathia vaginalis sp. nov. with the type strain DSM 16631T (=CCUG 52977T=CCUG 52889AT) and a second strain DSM 16630 (=CCUG 52976=CCUG 52888) that were both isolated from bloodstream infections in women with puerperal fever in France. The G+C content of the DNA of the type strain is 28.4 mol% and the genome size is 1.28 Mbp. Based on the observed extremely high similarities of genotypic and phenotypic traits of the novel proposed species to those reported for 'Sneathia amnii', we recommend using this new name in all further publications on this taxon.

PMID:33616512 | DOI:10.1099/ijsem.0.004663

ISME J. 2021 Feb 21. doi: 10.1038/s41396-021-00919-9. Online ahead of print.

ABSTRACT

Early evolution of mutualism is characterized by big and predictable adaptive changes, including the specialization of interacting partners, such as through deleterious mutations in genes not required for metabolic cross-feeding. We sought to investigate whether these early mutations improve cooperativity by manifesting in synergistic epistasis between genomes of the mutually interacting species. Specifically, we have characterized evolutionary trajectories of syntrophic interactions of Desulfovibrio vulgaris (Dv) with Methanococcus maripaludis (Mm) by longitudinally monitoring mutations accumulated over 1000 generations of nine independently evolved communities with analysis of the genotypic structure of one community down to the single-cell level. We discovered extensive parallelism across communities despite considerable variance in their evolutionary trajectories and the perseverance within many evolution lines of a rare lineage of Dv that retained sulfate-respiration (SR+) capability, which is not required for metabolic cross-feeding. An in-depth investigation revealed that synergistic epistasis across pairings of Dv and Mm genotypes had enhanced cooperativity within SR- and SR+ assemblages, enabling their coexistence within the same community. Thus, our findings demonstrate that cooperativity of a mutualism can improve through synergistic epistasis between genomes of the interacting species, enabling the coexistence of mutualistic assemblages of generalists and their specialized variants.

PMID:33612833 | DOI:10.1038/s41396-021-00919-9

J Clin Lipidol. 2021 Feb 9:S1933-2874(21)00028-3. doi: 10.1016/j.jacl.2021.01.011. Online ahead of print.

ABSTRACT

BACKGROUND: Plasma lipoproteins contain heterogeneous subclasses. Previous studies on the associations of the complement system with lipids and lipoproteins are mainly limited to the major lipid classes, and associations of complement with lipoprotein subclass characteristics remain unknown.

OBJECTIVE: We investigated the associations of C3 and other components of the alternative complement pathway with plasma lipoprotein subclass profile.

METHODS: Plasma complement concentrations (complement component 3 [C3], properdin, factor H, factor D, MASP-3, C3a, Bb), and lipoprotein subclass profile (as measured by nuclear magnetic resonance spectroscopy) were obtained in 523 participants (59.6 ± 6.9 years, 60.8% men) of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Multiple linear regression was used to investigate the associations of C3 (primary determinant) and other alternative pathway components (secondary determinants) with characteristics (particle concentration and size [main outcomes], and lipid contents [secondary outcomes]) of 14 lipoprotein subclasses, ranging from extremely large VLDL to small HDL (all standardized [std] values).

RESULTS: Participants with higher C3 concentrations had more circulating VLDL (stdβs ranging from 0.27 to 0.36), IDL and LDL (stdβs ranging from 0.14 to 0.17), and small HDL (stdβ = 0.21). In contrast, they had fewer very large and large HDL particles (stdβs = -0.36). In persons with higher C3 concentrations, all lipoprotein subclasses were enriched in triglycerides. Similar but weaker associations were observed for properdin, factor H, factor D, and MASP-3, but not for C3a and Bb.

CONCLUSIONS: The alternative complement pathway, and most prominently C3, is associated with an adverse lipoprotein subclass profile that is characterized by more triglyceride-enriched lipoproteins but fewer large HDL.

PMID:33612457 | DOI:10.1016/j.jacl.2021.01.011

Hum Immunol. 2021 Feb 18:S0198-8859(21)00045-8. doi: 10.1016/j.humimm.2021.02.005. Online ahead of print.

ABSTRACT

Nanopore sequencing has been investigated as a rapid and cost-efficient option for HLA typing in recent years. Despite the lower raw read accuracy, encouraging typing accuracy has been reported, and long reads from the platform offer additional benefits of the improved phasing of distant variants. The newly released R10.3 flow cells are expected to provide higher read-level accuracy than previous chemistries. We examined the performance of R10.3 flow cells on the MinION device in HLA typing after enrichment of target genes by multiplexed PCR. We also aimed to mimic a 1-day workflow with 8-24 samples per sequencing run. A diverse collection of 102 unique samples were typed for HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3/4/5 loci. The concordance rates at 2-field and 3-field resolutions were 99.5% (1836 alleles) and 99.3% (1710 alleles). We also report important quality metrics from these sequencing runs. Continued research and independent validations are warranted to increase the robustness of nanopore-based HLA typing for broad clinical application.

PMID:33612390 | DOI:10.1016/j.humimm.2021.02.005

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"systems biology"

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J Plant Physiol. 2021 Jan 26;258-259:153375. doi: 10.1016/j.jplph.2021.153375. Online ahead of print.

ABSTRACT

Water deficiency caused by drought is one of the severe environmental conditions limiting plant growth, development, and yield. In this review article, we will summarize the changes in transcription, metabolism, and phytohormones under drought stress conditions and show the key transcription factors in these processes. We will also highlight the recent attempts to enhance stress tolerance without growth retardation and discuss the perspective on the development of stress adapted crops by engineering transcription factors.

PMID:33609854 | DOI:10.1016/j.jplph.2021.153375

Metabolomics. 2021 Feb 20;17(3):28. doi: 10.1007/s11306-021-01776-5.

ABSTRACT

INTRODUCTION: Glufosinate resistant (GR) buffalo grasses were genetically modified to resist the broad-spectrum herbicide, glufosinate by inserting a novel pat gene into its genome. This modification results in a production of additional phosphinothricin acetyltransferase (PAT) to detoxify the deleterious effects of glufosinate. The GR grasses and its associated herbicide form a modern, weeding program, to eradicate obnoxious weeds in turf lawn without damaging the grasses at relatively low costs and labor. As with several principal crops which are genetically modified to improve agricultural traits, biosafety of the GR buffalo grasses is inevitably expected to become a public concern. For the first time, we had previously examined the metabolome of glufosinate-resistant buffalo grasses, using a GC-MS untargeted approach to assess the risk of GR as well as identify any pleotropic effects arising from the genetically modification process. In this paper, an untargeted high-resolution LC-MS (LC-HRMS) untargeted metabolomics approach was carried out to complement our previous findings with respect to GR and wild type (WT) buffalo grasses.

OBJECTIVE: One of the major aims of this present work was to compare GR to WT buffalo grasses by including the detection of the secondary metabolome and determine any unprecedented metabolic changes.

METHODS: Eight-week old plants of 4 GR buffalo grasses, (93-1A, 93-2B, 93-3 C and 93-5A) and 3 wild type varieties (WT 8-4A, WT 9-1B and WT 9-1B) were submerged in either 5 % v/v of glufosinate or distilled water 3 days prior to a LC-HRMS based untargeted metabolomics analysis (glufosinate-treated or control, samples, respectively). An Ultra-High-Performance Liquid Chromatography (UHPLC) system coupled to a Velos Pro Orbitrap mass spectrometer system was employed to holistically measure the primary and secondary metabolome of both GR and WT buffalo grasses either treated with or without glufosinate and subsequently apply several bioinformatic tools including the automated pathway analysis algorithm, mummichog.

RESULTS: LC-HRMS untargeted based metabolomics clearly identified that the global metabolite pools of both GR and WT cultivars were highly similar, providing strong, supporting evidence of substantial equivalence between the GR and WT varieties. These findings indicate that if any associated risks to these GR grasses were somehow present, the risk would be within those acceptable ranges present in the WT. Additionally, mummichog-based pathway analysis indicated that phenylalanine metabolism and the TCA cycle were significantly impacted by glufosinate treatment in the WT cultivar. It was possible that alterations in the relative concentrations of several intermediates in these pathways were likely due to glufosinate-induced production of secondary metabolites to enhance plant defense mechanisms against herbicidal stress at the expense of primary metabolism.

CONCLUSIONS: GR buffalo grasses were found to be near identical to its WT comparator based on this complementary LC-HRMS based untargeted metabolomics. Therefore, these results further support the safe use of these GR buffalo grasses with substantial evidence. Interestingly, despite protected by PAT, GR buffalo grasses still demonstrated the response to glufosinate treatment by up-regulating some secondary metabolite-related pathways.

PMID:33609206 | DOI:10.1007/s11306-021-01776-5

Plant Cell Environ. 2021 Feb 19. doi: 10.1111/pce.14034. Online ahead of print.

ABSTRACT

Nitrogen sources are all converted into ammonium/ia as a first step of assimilation. It is reasonable to expect that molecular components involved in the transport of ammonium/ia across biological membranes connect with the regulation of both nitrogen and central metabolism. We applied both genetic (i.e., Δamt mutation) and environmental treatments to a target biological system, the cyanobacterium Anabaena sp. PCC 7120. The aim was to both perturb nitrogen metabolism and induce multiple inner nitrogen states, respectively, followed by targeted quantification of key proteins, metabolites and enzyme activities. The absence of AMT transporters triggered a substantial whole-system response, affecting enzyme activities and quantity of proteins and metabolites, spanning nitrogen and carbon metabolism. Moreover, the Δamt strain displayed a molecular fingerprint indicating nitrogen-deficiency even under nitrogen replete conditions. Contrasting with such dynamic adaptations was the striking near-complete lack of an externally measurable altered phenotype. We conclude that this species evolved a highly robust and adaptable molecular network to maintain homeostasis, resulting in substantial internal but minimal external perturbations. This analysis provides evidence for a potential role of AMT transporters in the regulatory/signalling network of nitrogen metabolism and the existence of a novel fourth regulatory mechanism controlling glutamine synthetase activity. This article is protected by copyright. All rights reserved.

PMID:33608943 | DOI:10.1111/pce.14034

Mikrochim Acta. 2021 Feb 19;188(3):92. doi: 10.1007/s00604-021-04733-0.

ABSTRACT

A screen-printed electrode (SPE) is described modified with sulfur-tin oxide nanoparticles (S@SnO2NP) for the determination of entacapone (ENT) in the presence of other medicines against Parkinson's disease (PD). The S@SnO2NP was synthesized through the hydrothermal method and used in the modification of the SPE. The smart utilization of the S@SnO2NP and the SPE provided excellent properties such as high surface area and current density amplification by embedding an efficient sensing interface for highly selective electrochemical measurement. Under optimized experimental conditions, the anodic peak current related to the ENT oxidation onto the sensor surface at 0.46 V presented a linear response towards different ENT concentration sin the range 100 nM to 75 μM. The limit of detection (LOD) and electrochemical sensitivity were estimated to be 0.010 μM and 2.27 μA·μM-1·cm-2, respectively. The applicability of the sensor was evaluated during ENT determination in the presence of other conventional medicines againts, including levodopa (LD), carbidopa (CD), and pramipexole (PPX). The results of the analysis of human urine and pharmaceutical formulation as real samples using the developed sensor were in good agreement withre sults of high-performance liquid chromatography (HPLC) as a standard method. These findings demonstrated that the strategy based on the SPE is a cost-effective platform creating a promising candidate for practical determination of ENT in routine clinical testing.Graphical abstract.

PMID:33608774 | DOI:10.1007/s00604-021-04733-0

Clin Infect Dis. 2021 Feb 20:ciab154. doi: 10.1093/cid/ciab154. Online ahead of print.

ABSTRACT

BACKGROUND: Data on the characteristics of COVID-19 patients disaggregated by race/ethnicity remain limited. We evaluated the sociodemographic and clinical characteristics of patients across racial/ethnic groups and assessed their associations with COVID-19 outcomes.

METHODS: This retrospective cohort study examined 629,953 patients tested for SARS-CoV-2 in a large health system spanning California, Oregon, and Washington between March 1 and December 31, 2020. Sociodemographic and clinical characteristics were obtained from electronic health records. Odds of SARS-CoV-2 infection, COVID-19 hospitalization, and in-hospital death were assessed with multivariate logistic regression.

RESULTS: 570,298 patients with known race/ethnicity were tested for SARS-CoV-2, of whom 27.8% were non-White minorities. 54,645 individuals tested positive, with minorities representing 50.1%. Hispanics represented 34.3% of infections but only 13.4% of tests. While generally younger than White patients, Hispanics had higher rates of diabetes but fewer other comorbidities. 8,536 patients were hospitalized and 1,246 died, of whom 56.1% and 54.4% were non-White, respectively. Racial/ethnic distributions of outcomes across the health system tracked with state-level statistics. Increased odds of testing positive and hospitalization were associated with all minority races/ethnicities. Hispanic patients also exhibited increased morbidity, and Hispanic race/ethnicity was associated with in-hospital mortality (OR: 1.39 [95% CI: 1.14-1.70]).

CONCLUSION: Major healthcare disparities were evident, especially among Hispanics who tested positive at a higher rate, required excess hospitalization and mechanical ventilation, and had higher odds of in-hospital mortality despite younger age. Targeted, culturally-responsive interventions and equitable vaccine development and distribution are needed to address the increased risk of poorer COVID-19 outcomes among minority populations.

PMID:33608710 | DOI:10.1093/cid/ciab154

Nat Cell Biol. 2021 Feb 19. doi: 10.1038/s41556-021-00650-9. Online ahead of print.

NO ABSTRACT

PMID:33608689 | DOI:10.1038/s41556-021-00650-9

Sci Rep. 2021 Feb 19;11(1):4232. doi: 10.1038/s41598-021-82707-1.

ABSTRACT

Maoto, a traditional kampo medicine, has been clinically prescribed for influenza infection and is reported to relieve symptoms and tissue damage. In this study, we evaluated the effects of maoto as an herbal multi-compound medicine on host responses in a mouse model of influenza infection. On the fifth day of oral administration to mice intranasally infected with influenza virus [A/PR/8/34 (H1N1)], maoto significantly improved survival rate, decreased viral titer, and ameliorated the infection-induced phenotype as compared with control mice. Analysis of the lung and plasma transcriptome and lipid mediator metabolite profile showed that maoto altered the profile of lipid mediators derived from ω-6 and ω-3 fatty acids to restore a normal state, and significantly up-regulated the expression of macrophage- and T-cell-related genes. Collectively, these results suggest that maoto regulates the host's inflammatory response by altering the lipid mediator profile and thereby ameliorating the symptoms of influenza.

PMID:33608574 | DOI:10.1038/s41598-021-82707-1

Nat Commun. 2021 Feb 19;12(1):1147. doi: 10.1038/s41467-021-21385-z.

ABSTRACT

Within a short period of time, COVID-19 grew into a world-wide pandemic. Transmission by pre-symptomatic and asymptomatic viral carriers rendered intervention and containment of the disease extremely challenging. Based on reported infection case studies, we construct an epidemiological model that focuses on transmission around the symptom onset. The model is calibrated against incubation period and pairwise transmission statistics during the initial outbreaks of the pandemic outside Wuhan with minimal non-pharmaceutical interventions. Mathematical treatment of the model yields explicit expressions for the size of latent and pre-symptomatic subpopulations during the exponential growth phase, with the local epidemic growth rate as input. We then explore reduction of the basic reproduction number R0 through specific transmission control measures such as contact tracing, testing, social distancing, wearing masks and sheltering in place. When these measures are implemented in combination, their effects on R0 multiply. We also compare our model behaviour to the first wave of the COVID-19 spreading in various affected regions and highlight generic and less generic features of the pandemic development.

PMID:33608519 | DOI:10.1038/s41467-021-21385-z

Cell Death Dis. 2021 Feb 19;12(2):201. doi: 10.1038/s41419-021-03489-y.

ABSTRACT

Because of the lack of sensitivity to radiotherapy and chemotherapy, therapeutic options for renal clear cell carcinoma (KIRC) are scarce. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of cancer. However, their functional roles and upstream mechanisms in KIRC remain largely unknown. Exploring the functions of potential essential lncRNAs may lead to the discovery of novel targets for the diagnosis and treatment of KIRC. Here, according to the integrated analysis of RNA sequencing and survival data in TCGA-KIRC datasets, cyclin-dependent kinase inhibitor 2B antisense lncRNA (CDKN2B-AS1) was discovered to be the most upregulated among the 14 lncRNAs that were significantly overexpressed in KIRC and related to shorter survival. Functionally, CDKN2B-AS1 depletion suppressed cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, CDKN2B-AS1 exerted its oncogenic activity by recruiting the CREB-binding protein and SET and MYND domain-containing 3 epigenetic-modifying complex to the promoter region of Ndc80 kinetochore complex component (NUF2), where it epigenetically activated NUF2 transcription by augmenting local H3K27ac and H3K4me3 modifications. Moreover, we also showed that CDKN2B-AS1 interacted with and was stabilized by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal protein showing increased levels in KIRC. The Kaplan-Meier method and receiver operating curve analysis revealed that patients whose IGF2BP3, CDKN2B-AS1 and NUF2 are all elevated showed the shortest survival time, and the combined panel (containing IGF2BP3, CDKN2B-AS1, and NUF2) possessed the highest accuracy in discriminating high-risk from low-risk KIRC patients. Thus, we conclude that the stabilization of CDKN2B-AS1 by IGF2BP3 drives the malignancy of KIRC through epigenetically activating NUF2 transcription and that the IGF2BP3/CDKN2B-AS1/NUF2 axis may be an ideal prognostic and diagnostic biomarker and therapeutic target for KIRC.

PMID:33608495 | DOI:10.1038/s41419-021-03489-y