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Fusarium vorosii (Fv) is one of the least studied species of the Fusarium graminearum species complex, a major plant pathogen causing Fusarium head blight (FHB) in a variety of crops. In this study, we isolated 12 strains of Fv from cereal samples with FHB symptoms and gramineous weeds. Trichothecene genotyping of Fv strains showed that 10 strains were nivalenol (NIV) type and 2 strains were 15-acetyldeoxynivalenol (15ADON) type. Fv strains have similar mycological characteristics to Fusarium asiaticum, a major FHB pathogen of rice in Asia, however, asexual sporulation was at least 100 to 1,000 times higher in Fv. In comparison of pathogenicity, the Fv-15ADON type was more pathogenic than the NIV type in both rice and wheat, and had a similar level of pathogenicity as the F. asiaticum-NIV type. Among the 12 Fv strains, two representative ones, Fv-NIV type RN1 and Fv-15ADON type W15A1, were selected and their whole genomes were sequenced and analyzed. Complete genome sequences of two Fv strains, RN1 and W15A1, were assembled at the chromosome level with high quality compared to known Fv genomes. The genome data of the two Fv strains were compared with the reference strains already known. As a result of comparative genome analysis, it was found that they are phylogenetically related according to the trichothecene biosynthetic gene cluster, that is, toxin chemotype. Through this study, we provided important information about Fv species that can be potential pathogens in domestic crops about biological and genomic characteristics.

Abstract Seed microbial communities have been known to have a crucial role in the life cycle of a plant. In this study, we examined the distribution of the fungal communities in three compartments (husk, brown rice, and milled rice) of the fourteen rice seed samples. Ten fungal genera distributed throughout the three compartments of the rice seeds were identified as the core mycobiome of the rice seeds, regardless of collecting regions or cultivars. Based on the diversity analysis, the distribution of the fungal community in milled rice was found to be more diversified, evenly distributed, and differently clustered from the other two compartments. Among the core mycobiome, Moesziomyces dominated almost 80% of the fungal communities in the outer compartments of rice seeds, whereas the abundances of other endophytic pathogenic fungi declined. Our results provide that antagonistic yeast Moesziomyces may be able to control the endogenous pathogenic fungal communities in rice seeds, hence maintaining the quality of rice seeds. In addition, the distribution of fungal communities differs depending on the rice seed’s compartment, indicating that the compartment can affect the distribution of the seed microbial community.

Head blight is a serious fungal disease that results in yield loss and mycotoxin contamination in cereal crops worldwide. Head blight is primarily caused by members of the Fusarium graminearum species complex (FGSC), which consists of at least 16 species, including Fusarium asiaticum and Fusarium graminearum. FGSC members produce trichothecene mycotoxins and can be divided into four groups (chemotypes) depending on the type of trichothecenes produced: NIV (production of nivalenol), 3ADON (production of 3-acetyldeoxynivalenol), 15ADON (production of 15-acetyldeoxynivalenol), and NX-2 (production of 3α-acetoxy, 7α, 15-dihydroxy-12, and 13-epoxytrichothe-9-ene). Whereas F. graminearum mainly causes head blight in wheat-producing areas, F. asiaticum is associated primarily with rice head blight in eastern Asia. To date, the NCBI database archives 116 assembled genome sequences of F. graminearum, but only four accessions correspond to F. asiaticum. Accessions for three F. graminearum strains (PH-1 = NRRL 31084, CS3005, and FG-12) are chromosome assemblies (i.e., include contigs/scaffolds consisting of full-length or nearly full-length chromosomes), but none of the F. asiaticum accessions is a chromosome assembly. This announcement reports the assembled genome sequences of nine F. asiaticum strains and seven F. graminearum strains isolated from rice, wheat, barley, and other gramineous plants in Korea and China. [Figure: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract The industrial potential of Saccharomyces cerevisiae has extended beyond its traditional use in fermentation to various applications, including recombinant protein production. Herein, comparative genomics was performed with three industrial S. cerevisiae strains and revealed a heterozygous diploid genome for the 98‐5 and KSD‐YC strains (exploited for rice wine fermentation) and a haploid genome for strain Y2805 (used for recombinant protein production). Phylogenomic analysis indicated that Y2805 was closely associated with the reference strain S288C, whereas KSD‐YC and 98‐5 were grouped with Asian and European wine strains, respectively. Particularly, a single nucleotide polymorphism (SNP) in FDC1, involved in the biosynthesis of 4‐vinylguaiacol (4‐VG, a phenolic compound with a clove‐like aroma), was found in KSD‐YC, consistent with its lack of 4‐VG production. Phenotype microarray (PM) analysis showed that KSD‐YC and 98‐5 displayed broader substrate utilization than S288C and Y2805. The SNPs detected by genome comparison were mapped to the genes responsible for the observed phenotypic differences. In addition, detailed information on the structural organization of Y2805 selection markers was validated by Sanger sequencing. Integrated genomics and PM analysis elucidated the evolutionary history and genetic diversity of industrial S. cerevisiae strains, providing a platform to improve fermentation processes and genetic manipulation.

Abstract Honeybees are one of the most environmentally important insects, as their pollination of various plant species contributes to the balance among different ecosystems. It has been studied extensively for their unique attribute of forming a caste society. Unlike other insects, honeybees communicate socially by secreting pheromones or by exhibiting specific patterns of motion. In the honeybee industry, the Asian honeybees (Apis cerana) and the Western honeybees (Apis mellifera) are dominant species. However, molecular research on the transcriptomes of A. cerana has not been studied as extensively as those of A. mellifera. Therefore, in this study, caste-specific transcriptional differences were analyzed, which provides a comprehensive analysis of A. cerana. In our dataset, we analyzed gene expression profiles using organs from worker, drone, and queen bees. This gene-expression profile helped us obtain more detailed information related to organ-specific genes, immune response, detoxification mechanisms, venom-specific genes, and ovary development. From our result, we found 4096 transcripts representing different gene-expression pattern in each organ. Our results suggest that caste-specific transcripts of each organ were expressed differently even under natural conditions. These transcriptome-wide analyses provide new insights into A. cerana and that promote honeybee research and conservation.

Bacteria often change their genetic and physiological traits to survive in harsh environments. To determine whether, in various strains of Burkholderia glumae, genomic diversity is associated with the ability to adapt to ever-changing environments, whole genomes of 44 isolates from different hosts and regions were analyzed. Whole-genome phylogenetic analysis of the 44 isolates revealed six clusters and two divisions. While all isolates possessed chromosomes 1 and 2, strains BGR80S and BGR81S had one chromosome resulting from the merging of the two chromosomes. Upon comparison of genomic structures to the prototype BGR1, inversions, deletions, and rearrangements were found within or between chromosomes 1 and/or 2 in the other isolates. When three isolates—BGR80S, BGR15S, and BGR21S, representing clusters III, IV, and VI, respectively—were grown in Luria-Bertani medium, spontaneous null mutations were identified in qsmR encoding a quorum-sensing master regulator. Six days after subculture, qsmR mutants were found at detectable frequencies in BGR15S and BGR21S, and reached approximately 40% at 8 days after subculture. However, the qsmR mutants appeared 2 days after subculture in BGR80S and dominated the population, reaching almost 80%. No qsmR mutant was detected at detectable frequency in BGR1 or BGR13S. The spontaneous qsmR mutants outcompeted their parental strains in the co-culture. Daily addition of glucose or casamino acids to the batch cultures of BGR80S delayed emergence of qsmR mutants and significantly reduced their incidence. These results indicate that spontaneous qsmR mutations are correlated with genomic structures and nutritional conditions.

Abstract Background Nitrogen (N) is a key macronutrient essential for plant growth, and its availability has a strong influence on crop development. The application of synthetic N fertilizers on crops has increased substantially in recent decades; however, the applied N is not fully utilized due to the low N use efficiency of crops. To overcome this limitation, it is important to understand the genome-wide responses and functions of key genes and potential regulatory factors in N metabolism. Results Here, we characterized changes in the rice (Oryza sativa) transcriptome, including genes, newly identified putative long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) and their target mRNAs in response to N starvation using four different transcriptome approaches. Analysis of rice genes involved in N metabolism and/or transport using strand-specific RNA-Seq identified 2588 novel putative lncRNA encoding loci. Analysis of previously published RNA-Seq datasets revealed a group of N starvation-responsive lncRNAs showing differential expression under other abiotic stress conditions. Poly A-primed sequencing (2P-Seq) revealed alternatively polyadenylated isoforms of N starvation-responsive lncRNAs and provided precise 3′ end information on the transcript models of these lncRNAs. Analysis of small RNA-Seq data identified N starvation-responsive miRNAs and down-regulation of miR169 family members, causing de-repression of NF-YA, as confirmed by strand-specific RNA-Seq and qRT-PCR. Moreover, we profiled the N starvation-responsive down-regulation of root-specific miRNA, osa-miR444a.4-3p, and Degradome sequencing confirmed MADS25 as a novel target gene. Conclusions In this study, we used a combination of multiple RNA-Seq analyses to extensively profile the expression of genes, newly identified lncRNAs, and microRNAs in N-starved rice roots and shoots. Data generated in this study provide an in-depth understanding of the regulatory pathways modulated by N starvation-responsive miRNAs. The results of comprehensive, large-scale data analysis provide valuable information on multiple aspects of the rice transcriptome, which may be useful in understanding the responses of rice plants to changes in the N supply status of soil.

The prognosis and treatment of gastric cancer is complicated by heterogeneity. Here, the authors reveal two molecular subtypes, the mesenchymal subtype associated with poor survival and chemoresistance, and the epithelial phenotype associated with better survival and sensitivity to chemotherapy.

Abstract Epigenetic gene regulation is essential for developmental processes. Eggless (Egg), the Drosophila orthologue of the mammalian histone methyltransferase, SETDB1, is known to be involved in the survival and differentiation of germline stem cells and piRNA cluster transcription during Drosophila oogenesis; however the detailed mechanisms remain to be determined. Here, using high-throughput RNA sequencing, we investigated target genes regulated by Egg in an unbiased manner. We show that Egg plays diverse roles in particular piRNA pathway gene expression, some long non-coding RNA expression, apoptosis-related gene regulation, and Decapentaplegic (Dpp) signaling during Drosophila oogenesis. Furthermore, using genetic and cell biological approaches, we demonstrate that ectopic upregulation of dpp caused by loss of Egg in the germarium can trigger apoptotic cell death through activation of two pro-apoptotic genes, reaper and head involution defective. We propose a model in which Egg regulates germ cell differentiation and apoptosis through canonical and noncanonical Dpp pathways in Drosophila oogenesis.

Arsenite-resistance protein 2 (Ars2) is an important nuclear protein involved in various RNA metabolisms in animals and plants, but no Ars2 ortholog has been studied in filamentous fungi. Although it is an essential gene in most model eukaryotes, FgARS2 null mutants were viable in the plant pathogenic fungus Fusarium graminearum. The deletion of FgARS2 resulted in pleiotropic defects in various fungal developmental processes. Fgars2 mutants were irregular in nuclear division, and conidial germination was significantly retarded, causing the fungus to manifest its hypersensitive phenotypes under DNA damage stress. While FgARS2 deletion caused abnormal morphologies of ascospores and defective ascospore discharge, our data revealed that FgARS2 was not closely involved in small-non-coding RNA production in F. graminearum. The dominant nuclear localization of FgArs2-green fluorescent proteins (GFP) and abnormal nuclear division in FgARS2 deletion mutant implicated that FgArs2 functions in the nucleus. Intriguingly, we found that FgArs2 established a robust physical interaction with the cap binding complex (CBC) to form a tertiary complex CBC-Ars2 (CBCA), and disruption of any CBCA complex subunit drastically attenuated the virulence of F. graminearum. The results of the study indicate that Ars2 regulates fungal development, stress response, and pathogenesis via interaction with CBC in F. graminearum and provide a novel insight into understanding of the biological functions of Ars2 in filamentous fungi.

Despite the fact that a large number of miRNA sequences have been determined in diverse plant species, reports demonstrating the functional roles of miRNAs in the plant response to pathogens are severely limited. Here, Arabidopsis thaliana miRNA844 (miR844) was investigated for its functional role in the defense response to diverse pathogens. Transgenic Arabidopsis plants overexpressing miR844 (35S::miR844) displayed much more severe disease symptoms than the wild-type plants when challenged with the bacterium Pseudomonas syringae pv. tomato DC3000 or the fungus Botrytis cinerea. By contrast, a loss-of-function mir844 mutant showed an enhanced resistance against the pathogens. Although no cleavage was observed at the predicted cleavage site of the putative target mRNA, cytidinephosphate diacylglycerol synthase3 (CDS3), cleavage was observed at 6, 12, 21, or 52 bases upstream of the predicted cleavage site of CDS3 mRNA, and the level of CDS3 mRNA was downregulated by the overexpression of miR844, implying that miR844 influences CDS3 transcript level. To further confirm that the miR844-mediated defense response was due to the decrease in CDS3 mRNA level, the disease response of a CDS3 loss-of-function mutant was analyzed upon pathogen challenge. Increased susceptibility of both cds3 mutant and 35S::miR844 plants to pathogens confirmed that miR844 affected the defense response by downregulating CDS3 mRNA. The expression of miR844 was decreased, and the CDS3 transcript level increased upon pathogen challenge. Taken together, these results provide evidence that downregulation of miR844 and a concomitant increase in CDS3 expression is a defensive response of Arabidopsis to bacteria and fungi.

ABSTRACT Quorum sensing (QS) controls cooperative activities in many Proteobacteria. In some species, QS-dependent specific metabolism contributes to the stability of the cooperation. However, the mechanism by which QS and metabolic networks have coevolved to support stable public good cooperation and maintenance of the cooperative group remains unknown. Here we explored the underlying mechanisms of QS-controlled central metabolism in the evolutionary aspects of cooperation. In Burkholderia glumae, the QS-dependent glyoxylate cycle plays an important role in cooperativity. A bifunctional QS-dependent transcriptional regulator, QsmR, rewired central metabolism to utilize the glyoxylate cycle rather than the tricarboxylic acid cycle. Defects in the glyoxylate cycle caused metabolic imbalance and triggered high expression of the stress-responsive chaperonin GroEL. High-level expression of GroEL in glyoxylate cycle mutants interfered with the biosynthesis of a public resource, oxalate, by physically interrupting the oxalate biosynthetic enzyme ObcA. Under such destabilized cooperativity conditions, spontaneous mutations in the qsmR gene in glyoxylate cycle mutants occurred to relieve metabolic stresses, but these mutants lost QsmR-mediated pleiotropy. Overcoming the metabolic restrictions imposed on the population of cooperators among glyoxylate cycle mutants resulted in the occurrence and selection of spontaneous qsmR mutants despite the loss of other important functions. These results provide insight into how QS bacteria have evolved to maintain stable cooperation via QS-mediated metabolic coordination. IMPORTANCE We address how quorum sensing (QS) has coevolved with metabolic networks to maintain bacterial sociality. We found that QS-mediated metabolic rewiring is critical for sustainable bacterial cooperation in Burkholderia glumae. The loss of the glyoxylate cycle triggered the expression of the stress-responsive molecular chaperonin GroEL. Excessive biosynthesis of GroEL physically hampered biosynthesis of a public good, oxalate. This is one good example of how molecular chaperones play critical roles in bacterial cooperation. In addition, we showed that metabolic restrictions in the glyoxylate cycle acted as a selection pressure on metabolic networks; there were spontaneous mutations in the qsmR gene to relieve such stresses. However, the presence of spontaneous qsmR mutants had tragic consequences for a cooperative population of B. glumae due to failure of qsmR-dependent activation of public good biosynthesis. These results provide a good example of a bacterial strategy for robust cooperation via QS-mediated metabolic rewiring.

Various ascomycete fungi possess sex-specific molecular mechanisms, such as repeat-induced point mutations, meiotic silencing by unpaired DNA, and unusual adenosine-to-inosine RNA editing, for genome defense or gene regulation. Using a combined analysis of functional genetics and deep sequencing of small noncoding RNA (sRNA), mRNA, and the degradome, we found that the sex-specifically induced exonic small interference RNA (ex-siRNA)-mediated RNA interference (RNAi) mechanism has an important role in fine-tuning the transcriptome during ascospore formation in the head blight fungus Fusarium graminearum. Approximately one-third of the total sRNAs were produced from the gene region, and sRNAs with an antisense direction or 5'-U were involved in post-transcriptional gene regulation by reducing the stability of the corresponding gene transcripts. Although both Dicers and Argonautes partially share their functions, the sex-specific RNAi pathway is primarily mediated by FgDicer1 and FgAgo2, while the constitutively expressed RNAi components FgDicer2 and FgAgo1 are responsible for hairpin-induced RNAi. Based on our results, we concluded that F. graminearum primarily utilizes ex-siRNA-mediated RNAi for ascosporogenesis but not for genome defenses and other developmental stages. Each fungal species appears to have evolved RNAi-based gene regulation for specific developmental stages or stress responses. This study provides new insights into the regulatory role of sRNAs in fungi and other lower eukaryotes.

To compare capecitabine and oxaliplatin (XELOX) with S-1 as adjuvant chemotherapy in stage III gastric cancer after D2 gastrectomy.Clinical data from 206 patients who received XELOX or S-1 regimens as adjuvant chemotherapy in stage III gastric cancer were collected. Patients were divided into 2 groups according to regimen; the groups were XELOX (n = 114) and S-1 monotherapy (n = 92).3-year disease-free survival (DFS) was higher in the S-1 group than in the XELOX group (66.6% vs 59.1%; p = 0.636). 3-year overall survival (OS) was 75.6% in the S-1 group and 69.6% in the XELOX group (p = 0.495). But, the difference was not statistically significant. Especially, for patients with stage IIIC disease, 3-year overall survival was 55.2% in the XELOX group and 39.0% in the S-1 group (hazard ratio, HR 0.50, 95% confidence interval, CI 0.23-1.10; p = 0.075). In multivariate analysis, N stage (HR, 5.639; 95% CI, 1.297-24.522; p = 0.021) and cycle completion as planned (HR, 5.734; 95% CI, 3.007-10.936; p

Ethylene is one of the most important hormones for plant developmental processes and stress responses. However, the phosphorylation regulation in the ethylene signaling pathway is largely unknown. Here we report the phosphorylation of cap binding protein 20 (CBP20) at Ser245 is regulated by ethylene, and the phosphorylation is involved in root growth. The constitutive phosphorylation mimic form of CBP20 (CBP20S245E or CBP20S245D), while not the constitutive de-phosphorylation form of CBP20 (CBP20S245A) is able to rescue the root ethylene responsive phenotype of cbp20. By genome wide study with ethylene regulated gene expression and microRNA (miRNA) expression in the roots and shoots of both Col-0 and cbp20, we found miR319b is up regulated in roots while not in shoots, and its target MYB33 is specifically down regulated in roots with ethylene treatment. We described both the phenotypic and molecular consequences of transgenic over-expression of miR319b. Increased levels of miR319b (miR319bOE) leads to enhanced ethylene responsive root phenotype and reduction of MYB33 transcription level in roots; over expression of MYB33, which carrying mutated miR319b target site (mMYB33) in miR319bOE is able to recover both the root phenotype and the expression level of MYB33. Taken together, we proposed that ethylene regulated phosphorylation of CBP20 is involved in the root growth and one pathway is through the regulation of miR319b and its target MYB33 in roots.

Transcriptome analysis is a widely used approach to study the molecular mechanisms underlying development and the responses of fungi to environmental cues. However, it is difficult to obtain cells with a homogeneous status from the sexually-induced culture of the plant pathogenic fungus Fusarium graminearum. In this study, we provided phenotypic and genetic evidence to show that the current conditions applied for perithecia induction inevitably highly induced asexual sporulation in this fungus. We also found that hundreds of genes under the control of the conidiation-specific gene ABAA were unnecessarily upregulated after perithecia induction. Deletion of ABAA specifically blocked conidia production in both the wild-type strain and sexually-defective mutants during sexual development. Taken together, our results suggest that the abaA strain could be used as a background strain for studies of the initial stages of perithecia production in F. graminearum. Further comparative transcriptome analysis between the abaA mutant and the sexually-defective transcription factor mutant carrying the ABAA deletion would contribute to the construction of the genetic networks involved in perithecia development in F. graminearum.

MicroRNAs (miRNAs) are a class of non-coding RNAs approximately 21 nt in length which play important roles in regulating gene expression in plants. Although many miRNA studies have focused on a few model plants, miRNAs and their target genes remain largely unknown in hot pepper (Capsicum annuum), one of the most important crops cultivated worldwide. Here, we employed high-throughput sequencing technology to identify miRNAs in pepper extensively from 10 different libraries, including leaf, stem, root, flower, and six developmental stage fruits. Based on a bioinformatics pipeline, we successfully identified 29 and 35 families of conserved and novel miRNAs, respectively. Northern blot analysis was used to validate further the expression of representative miRNAs and to analyze their tissue-specific or developmental stage-specific expression patterns. Moreover, we computationally predicted miRNA targets, many of which were experimentally confirmed using 5' rapid amplification of cDNA ends analysis. One of the validated novel targets of miR-396 was a domain rearranged methyltransferase, the major de novo methylation enzyme, involved in RNA-directed DNA methylation in plants. This work provides the first reliable draft of the pepper miRNA transcriptome. It offers an expanded picture of pepper miRNAs in relation to other plants, providing a basis for understanding the functional roles of miRNAs in pepper.

BackgroundAlthough several prognostic genomic predictors have been identified from independent studies, it remains unclear whether these predictors are actually concordant with respect to their predictions for individual patients and which predictor performs best. We compared five prognostic genomic predictors, the V7RHS, the ColoGuideEx, the Meta163, the OncoDX, and the MDA114, in terms of predicting disease-free survival in two independent cohorts of patients with colorectal cancer.Study designUsing original classification algorithms, we tested the predictions of five genomic predictors for disease-free survival in two cohorts of patients with colorectal cancer (n = 229 and n = 168) and evaluated concordance of predictors in predicting outcomes for individual patients.ResultsWe found that only two predictors, OncoDX and MDA114, demonstrated robust performance in identifying patients with poor prognosis in 2 independent cohorts. These two predictors also had modest but significant concordance of predicted outcome (r>0.3, PConclusionsFurther validation of developed genomic predictors is necessary. Despite the limited number of genes shared by OncoDX and MDA114, individual-patient outcomes predicted by these two predictors were significantly concordant.

Fusarium graminearum (teleomorph Gibberella zeae) is a prominent pathogen that infects major cereal crops such as wheat, barley, and maize. Both sexual (ascospores) and asexual (conidia) spores are produced in F. graminearum. Since conidia are responsible for secondary infection in disease development, our objective of the present study was to reveal the molecular mechanisms underlying conidiogenesis in F. graminearum based on the framework previously described in Aspergillus nidulans. In this study, we firstly identified and functionally characterized the ortholog of AbaA, which is involved in differentiation from vegetative hyphae to conidia and known to be absent in F. graminearum. Deletion of abaA did not affect vegetative growth, sexual development, or virulence, but conidium production was completely abolished and thin hyphae grew from abnormally shaped phialides in abaA deletion mutants. Overexpression of abaA resulted in pleiotropic defects such as impaired sexual and asexual development, retarded conidium germination, and reduced trichothecene production. AbaA localized to the nuclei of phialides and terminal cells of mature conidia. Successful interspecies complementation using A. nidulans AbaA and the conserved AbaA-WetA pathway demonstrated that the molecular mechanisms responsible for AbaA activity are conserved in F. graminearum as they are in A. nidulans. Results from RNA-sequencing analysis suggest that AbaA plays a pivotal role in conidiation by regulating cell cycle pathways and other conidiation-related genes. Thus, the conserved roles of the AbaA ortholog in both A. nidulans and F. graminearum give new insight into the genetics of conidiation in filamentous fungi.

Fusarium graminearum is an important plant pathogen that causes head blight of major cereal crops. The fungus produces mycotoxins that are harmful to animal and human. In this study, a systematic analysis of 17 phenotypes of the mutants in 657 Fusarium graminearum genes encoding putative transcription factors (TFs) resulted in a database of over 11,000 phenotypes (phenome). This database provides comprehensive insights into how this cereal pathogen of global significance regulates traits important for growth, development, stress response, pathogenesis, and toxin production and how transcriptional regulations of these traits are interconnected. In-depth analysis of TFs involved in sexual development revealed that mutations causing defects in perithecia development frequently affect multiple other phenotypes, and the TFs associated with sexual development tend to be highly conserved in the fungal kingdom. Besides providing many new insights into understanding the function of F. graminearum TFs, this mutant library and phenome will be a valuable resource for characterizing the gene expression network in this fungus and serve as a reference for studying how different fungi have evolved to control various cellular processes at the transcriptional level.

Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future.Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern.We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

Research has been conducted on the enzymes that catalyze sequential reactions. The effect of the physical proximity of these enzymes has been tested.