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1.
Nature ; 623(7987): 633-642, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37938770

ABSTRACT

Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1-4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.


Subject(s)
Endogenous Retroviruses , Gene Silencing , Histones , Intracellular Signaling Peptides and Proteins , Lysine , Retroelements , Animals , Humans , Mice , Chromatin/genetics , Chromatin/metabolism , Co-Repressor Proteins/metabolism , Endogenous Retroviruses/genetics , Epigenesis, Genetic , Gene Expression Profiling , Genome/genetics , Histone Deacetylases/metabolism , Histones/metabolism , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lysine/metabolism , Methylation , Protein Domains , Retroelements/genetics , Terminal Repeat Sequences/genetics , Animals, Newborn , Cell Line
2.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Article in English | MEDLINE | ID: mdl-35217626

ABSTRACT

Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or mixed lineage leukemia (MLL) rearrangement (MLL-r) share transcriptomic profiles associated with stemness-related gene signatures and display poor prognosis. The molecular underpinnings of AML aggressiveness and stemness remain far from clear. Studies with EZH2 enzymatic inhibitors show that polycomb repressive complex 2 (PRC2) is crucial for tumorigenicity in NUP98-NSD1+ AML, whereas transcriptomic analysis reveal that Kdm5b, a lysine demethylase gene carrying "bivalent" chromatin domains, is directly repressed by PRC2. While ectopic expression of Kdm5b suppressed AML growth, its depletion not only promoted tumorigenicity but also attenuated anti-AML effects of PRC2 inhibitors, demonstrating a PRC2-|Kdm5b axis for AML oncogenesis. Integrated RNA sequencing (RNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and Cleavage Under Targets & Release Using Nuclease (CUT&RUN) profiling also showed that Kdm5b directly binds and represses AML stemness genes. The anti-AML effect of Kdm5b relies on its chromatin association and/or scaffold functions rather than its demethylase activity. Collectively, this study describes a molecular axis that involves histone modifiers (PRC2-|Kdm5b) for sustaining AML oncogenesis.


Subject(s)
Jumonji Domain-Containing Histone Demethylases/metabolism , Leukemia, Myeloid, Acute/pathology , Nuclear Proteins/metabolism , Polycomb Repressive Complex 2/metabolism , Repressor Proteins/metabolism , Animals , Carcinogenesis , Gene Expression Profiling , Histone Demethylases/metabolism , Humans , Leukemia, Myeloid, Acute/metabolism , Mice , Oncogene Proteins/metabolism , Polycomb Repressive Complex 2/antagonists & inhibitors , Protein Binding , Sequence Analysis, RNA/methods
3.
Nucleic Acids Res ; 50(19): 10929-10946, 2022 10 28.
Article in English | MEDLINE | ID: mdl-36300627

ABSTRACT

Enhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are crucial chromatin/gene regulators involved in the development and/or progression of prostate cancer, including advanced castration-resistant prostate cancer (CRPC). To sustain prostate tumorigenicity, EZH2 establishes non-canonical biochemical interaction with AR for mediating oncogene activation, in addition to its canonical role as a transcriptional repressor and enzymatic subunit of Polycomb Repressive Complex 2 (PRC2). However, the molecular basis underlying non-canonical activities of EZH2 in prostate cancer remains elusive, and a therapeutic strategy for targeting EZH2:AR-mediated oncogene activation is also lacking. Here, we report that a cryptic transactivation domain of EZH2 (EZH2TAD) binds both AR and AR spliced variant 7 (AR-V7), a constitutively active AR variant enriched in CRPC, mediating assembly and/or recruitment of transactivation-related machineries at genomic sites that lack PRC2 binding. Such non-canonical targets of EZH2:AR/AR-V7:(co-)activators are enriched for the clinically relevant oncogenes. We also show that EZH2TAD is required for the chromatin recruitment of EZH2 to oncogenes, for EZH2-mediated oncogene activation and for CRPC growth in vitro and in vivo. To completely block EZH2's multifaceted oncogenic activities in prostate cancer, we employed MS177, a recently developed proteolysis-targeting chimera (PROTAC) of EZH2. Strikingly, MS177 achieved on-target depletion of both EZH2's canonical (EZH2:PRC2) and non-canonical (EZH2TAD:AR/AR-V7:co-activators) complexes in prostate cancer cells, eliciting far more potent antitumor effects than the catalytic inhibitors of EZH2. Overall, this study reports a previously unappreciated requirement for EZH2TAD for mediating EZH2's non-canonical (co-)activator recruitment and gene activation functions in prostate cancer and suggests EZH2-targeting PROTACs as a potentially attractive therapeutic for the treatment of aggressive prostate cancer that rely on the circuits wired by EZH2 and AR.


Subject(s)
Enhancer of Zeste Homolog 2 Protein , Prostatic Neoplasms, Castration-Resistant , Receptors, Androgen , Humans , Male , Cell Line, Tumor , Chromatin/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Gene Expression Regulation, Neoplastic , Oncogenes , Polycomb Repressive Complex 2/genetics , Polycomb Repressive Complex 2/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Transcriptional Activation , Protein Isoforms
4.
Nucleic Acids Res ; 49(8): 4441-4455, 2021 05 07.
Article in English | MEDLINE | ID: mdl-33823544

ABSTRACT

Trimethylation of histone H3 lysine 27 (H3K27me3) is important for gene silencing and imprinting, (epi)genome organization and organismal development. In a prevalent model, the functional readout of H3K27me3 in mammalian cells is achieved through the H3K27me3-recognizing chromodomain harbored within the chromobox (CBX) component of canonical Polycomb repressive complex 1 (cPRC1), which induces chromatin compaction and gene repression. Here, we report that binding of H3K27me3 by a Bromo Adjacent Homology (BAH) domain harbored within BAH domain-containing protein 1 (BAHD1) is required for overall BAHD1 targeting to chromatin and for optimal repression of the H3K27me3-demarcated genes in mammalian cells. Disruption of direct interaction between BAHD1BAH and H3K27me3 by point mutagenesis leads to chromatin remodeling, notably, increased histone acetylation, at its Polycomb gene targets. Mice carrying an H3K27me3-interaction-defective mutation of Bahd1BAH causes marked embryonic lethality, showing a requirement of this pathway for normal development. Altogether, this work demonstrates an H3K27me3-initiated signaling cascade that operates through a conserved BAH 'reader' module within BAHD1 in mammals.


Subject(s)
Chromatin/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Histones/metabolism , Polycomb-Group Proteins/metabolism , Acetylation , Animals , Chromatin/genetics , Chromatin Assembly and Disassembly , Chromatin Immunoprecipitation Sequencing , Chromosomal Proteins, Non-Histone/genetics , Female , Gene Expression Profiling , Gene Ontology , HEK293 Cells , Humans , Male , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutagenesis, Site-Directed , Polycomb-Group Proteins/genetics , Protein Domains
5.
Nucleic Acids Res ; 49(9): 4971-4988, 2021 05 21.
Article in English | MEDLINE | ID: mdl-33849067

ABSTRACT

Castration-resistant prostate cancer (CRPC) is a terminal disease and the molecular underpinnings of CRPC development need to be better understood in order to improve its treatment. Here, we report that a transcription factor Yin Yang 1 (YY1) is significantly overexpressed during prostate cancer progression. Functional and cistrome studies of YY1 uncover its roles in promoting prostate oncogenesis in vitro and in vivo, as well as sustaining tumor metabolism including the Warburg effect and mitochondria respiration. Additionally, our integrated genomics and interactome profiling in prostate tumor show that YY1 and bromodomain-containing proteins (BRD2/4) co-occupy a majority of gene-regulatory elements, coactivating downstream targets. Via gene loss-of-function and rescue studies and mutagenesis of YY1-bound cis-elements, we unveil an oncogenic pathway in which YY1 directly binds and activates PFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced Warburg effect and malignant growth. Altogether, this study supports a master regulator role for YY1 in prostate tumorigenesis and reveals a YY1:BRD2/4-PFKP axis operating in advanced prostate cancer with implications for therapy.


Subject(s)
Gene Expression Regulation, Neoplastic , Phosphofructokinase-1, Type C/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , YY1 Transcription Factor/metabolism , Animals , Carcinogenesis , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Glycolysis , HEK293 Cells , Humans , Male , Mice, SCID , Phosphofructokinase-1, Type C/physiology , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Transcription Factors/metabolism , Transcriptional Activation , YY1 Transcription Factor/genetics , YY1 Transcription Factor/physiology
6.
Yi Chuan ; 45(7): 617-623, 2023 Jul 20.
Article in English | MEDLINE | ID: mdl-37503585

ABSTRACT

Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disease characterized by early hypotonia, and rapid progression to psychomotor development regression, pyramidal tract positivity, and spastic quadriplegia. In this report, we describe a Chinese patient with INAD who presented with hypotonia, delayed motor and language development, and subsequently improved with rehabilitation training. Genetic testing revealed that the patient had compound heterozygous PLA2G6 gene variants, with the heterozygous c.496dupG (p.Glu166fsTer32) variant inherited from her father and the heterozygous c.2189T>G (p.Met730Arg) variant inherited from her mother. The p.Met730Arg was a novel variant. The protein structure predicts that the structural stability of the mutant protein may change, and the in vivo experimental results show that the expression of the mutant protein decrease. This study enriches the PLA2G6 gene mutation spectrum, and improves the clinicians' diagnostic awareness of INAD.


Subject(s)
Neuroaxonal Dystrophies , Neurodegenerative Diseases , Humans , Child , Female , Neurodegenerative Diseases/genetics , Muscle Hypotonia/genetics , Genetic Testing , Mutation , Neuroaxonal Dystrophies/genetics
7.
Cancer Cell Int ; 21(1): 390, 2021 Jul 21.
Article in English | MEDLINE | ID: mdl-34289837

ABSTRACT

BACKGROUND: miR-198 is involved in the formation, migration, invasion, and metastasis of various malignant cancers. However, the function and mechanism of action of miR-198 in the tumorigenesis of renal cell carcinoma (RCC) remain elusive. Here, we aimed to explore the role of miR198 in RCC. METHODS: Immunohistochemistry was performed to estimate the level of survivin in RCC sections. Quantitative real-time polymerase chain reaction was performed to determine the expression level of miR-198 in fresh RCC tissues. Furthermore, the target relationship between miR-198 and BIRC5 was predicted using the TargetScanHuman 7.2 database and verified via dual-luciferase reporter assay and western blotting. The effects of miR-198 on the viability, apoptosis, invasion, and migration of A498 and ACHN cells were studied using Cell Counting Kit-8, flow cytometry, transwell migration assay, and wound healing assay, respectively. Additionally, a xenograft nude mouse model was established to evaluate the effect of miR-198 on RCC tumorigenesis. RESULTS: The expression levels of BIRC5 and miR-198 were respectively higher and lower in RCC tissues than those in normal adjacent tissues. Furthermore, miR-198 could inhibit luciferase activity and reduce the protein level of survivin without affecting the BIRC5 mRNA levels. miR-198 inhibited cell viability, migration, and invasion and promoted cell apoptosis; co-transfection with BIRC5 could rescue these effects. Moreover, miR-198 could repress tumor growth in the xenograft nude mouse model of RCC. CONCLUSIONS: Our study demonstrates that miR-198 suppresses RCC progression by targeting BIRC5.

8.
Arch Toxicol ; 95(3): 1081-1088, 2021 03.
Article in English | MEDLINE | ID: mdl-33398416

ABSTRACT

N6-methyladenosine (m6A) modification plays a vital regulatory role in tumorigenesis and development. In this study, we determined that the mRNA expression of IGF2BP1, IGF2BP2 and IGF2BP3, as the m6A modification genes, was significantly increased in gastric cancer (GC) tissues. Using a logistic regression model, we found that novel single-nucleotide polymorphism (SNP) rs9906944 C > T in IGF2BP1 was remarkably associated with a decreased risk of GC in discovery stage (odds ratio (OR) = 0.75, 95% confidence interval (95% CI): 0.60-0.93, P = 8.51 × 10-3). This finding was repeated in an independent Nanjing population (OR = 0.76, 95% CI: 0.59-0.98, P = 3.45 × 10-2). The combined analysis including 2900 GC cases and 3,536 controls confirmed the association between rs9906944 C > T and GC risk (OR = 0.75, 95% CI: 0.64-0.88, P = 5.76 × 10-4). Furthermore, we found that GC patients with higher IGF2BP1 mRNA expression level had prominent poorer overall survival (hazard ratio (HR) = 1.49, 95% CI: 1.16-1.91, logrank P = 1.50 × 10-3). For the first time, our findings suggested the importance of genetic variants in m6A regulators in GC and indicated that IGF2BP1 plays a crucial role in GC. Genetic variants in m6A modification genes may be used for GC risk prediction.


Subject(s)
Adenosine/analogs & derivatives , Asian People/genetics , RNA-Binding Proteins/genetics , Stomach Neoplasms/genetics , Adenosine/genetics , Case-Control Studies , Female , Genetic Predisposition to Disease , Genetic Variation , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Survival Rate
9.
Environ Microbiol ; 22(11): 4718-4731, 2020 11.
Article in English | MEDLINE | ID: mdl-32881227

ABSTRACT

To assess the comparability between taxonomic identification methods for phytoplankton, multiple approaches were used to characterize phytoplankton community composition within the Neuse River Estuary (NRE), North Carolina. Small subunit 18S rRNA gene sequencing and accessory pigment analysis displayed similar trends, indicating chlorophytes were the dominant microalgal group during most of the year, whereas results from microscopic cell counts, biovolume analysis and metatranscriptomics suggested diatom and dinoflagellate-dominated communities. Spatial environmental gradients drove variation in taxonomic composition due to preferences for specific environmental conditions among different microalgal groups. Cryptophytes were a greater proportion of the phytoplankton community within high nutrient, fresher environments whereas diatoms and dinoflagellates dominated higher salinity sections of the estuary. This study provides a detailed examination of phytoplankton communities associated with environmental gradients present in the NRE. The high level of taxonomic resolution offered by DNA sequencing (i.e., species to sub-species level) provides a better understanding of population dynamics at the base of estuarine food webs.


Subject(s)
Environmental Monitoring/methods , Estuaries , Eutrophication , Phytoplankton/classification , North Carolina , Phytoplankton/cytology , Phytoplankton/genetics , Phytoplankton/isolation & purification , Rivers/chemistry , Rivers/microbiology , Salinity , Spatio-Temporal Analysis
10.
Arch Toxicol ; 94(8): 2683-2690, 2020 08.
Article in English | MEDLINE | ID: mdl-32524153

ABSTRACT

The dysregulation of Ras/Raf/MEK/ERK pathway governs occurrence and progression of cancers. In previous studies, genome-wide association studies (GWAS) have identified multiple gene loci related to gastric cancer. However, a great many genetic loci have been missed due to multiple statistical comparisons of GWAS. In this study, Multi-marker Analysis of GenoMic Annotation (MAGMA) was applied to analyze genes in Ras/Raf/MEK/ERK pathway and their single nucleotide polymorphisms (SNPs) based on Chinese GWAS including 1625 gastric cancer cases and 2100 controls. The SNP effects on gastric cancer susceptibility were calculated on the basis of a logistic regression model. Expression quantitative trait loci (eQTL) analysis was performed based on the genotype-tissue expression (GTEx) project. We identified that three SNPs in MAP2K1, rs4287513, rs76906202 and rs11631448 were markedly associated with gastric cancer risk (rs4287513: OR = 1.30, 95% CI = 1.10-1.54, P = 1.92 × 10-3; rs76906202: OR = 0.87, 95% CI = 0.79-0.96, P = 3.72 × 10-3; rs11631448: OR = 1.21, 95% CI = 1.05-1.39, P = 6.74 × 10-3). All the loci were eQTLs for MAP2K1 in normal gastric samples. Moreover, the low expression of MAP2K1 was significantly associated with poor survival in gastric cancer patients. Thus, MAP2K1 might represent a key gene related to gastric cancer in Ras/Raf/MEK/ERK pathway, whereas SNPs in MAP2K1 confer gastric cancer susceptibility by having biological effects on the MAP2K1 expression.


Subject(s)
MAP Kinase Kinase 1/genetics , Polymorphism, Single Nucleotide , Stomach Neoplasms/genetics , Asian People/genetics , Case-Control Studies , China , Databases, Genetic , Extracellular Signal-Regulated MAP Kinases/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Phenotype , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Quantitative Trait Loci , Risk Assessment , Risk Factors , Signal Transduction , Stomach Neoplasms/enzymology , Stomach Neoplasms/ethnology
11.
Cancer ; 125(14): 2465-2473, 2019 07 15.
Article in English | MEDLINE | ID: mdl-30951202

ABSTRACT

BACKGROUND: Previous genome-wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values. METHODS: This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts. RESULTS: SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E-04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta-analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E-12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro-RNA-212-3p and then promoting GBA expression. CONCLUSION: rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR-212-3p from binding to GBA.


Subject(s)
CpG Islands/genetics , Genetic Predisposition to Disease/genetics , Glucosylceramidase/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Pseudogenes/genetics , Stomach Neoplasms/genetics , Aged , Case-Control Studies , Cell Movement/genetics , Cell Proliferation/genetics , Cells, Cultured , Cohort Studies , DNA Methylation , Female , Genome-Wide Association Study , Genotype , Glucosylceramidase/metabolism , Humans , Male , MicroRNAs/metabolism , Middle Aged , Prognosis , Stomach Neoplasms/pathology
12.
Mol Cancer ; 17(1): 87, 2018 05 02.
Article in English | MEDLINE | ID: mdl-29720189

ABSTRACT

BACKGROUND: Emerging evidence has shown that dysregulation function of long non-coding RNAs (lncRNAs) implicated in gastric cancer (GC). However, the role of the differentially expressed lncRNAs in GC has not fully explained. METHODS: LncRNA expression profiles were determined by lncRNA microarray in five pairs of normal and GC tissues, further validated in another 75 paired tissues by quantitative real-time PCR (qRT-PCR). Overexpression of lncRNA MT1JP was conducted to assess the effect of MT1JP in vitro and in vivo. The biological functions were demonstrated by luciferase reporter assay, western blotting and rescue experiments. RESULTS: LncRNA MT1JP was significantly lower in GC tissues than adjacent normal tissues, and higher MT1JP was remarkably related to lymph node metastasis and advance stage. Besides, GC patients with higher MT1JP expression had a well survival. Functionally, overexpression of lncRNA MT1JP inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro, and inhibited tumor growth and metastasis in vivo. Functional analysis showed that lncRNA MT1JP regulated FBXW7 expression by competitively binding to miR-92a-3p. MiR-92a-3p and down-regulated FBXW7 reversed cell phenotypes caused by lncRNA MT1JP by rescue analysis. CONCLUSION: MT1JP, a down-regulated lncRNA in GC, was associated with malignant tumor phenotypes and survival of GC. MT1JP regulated the progression of GC by functioning as a competing endogenous RNA (ceRNA) to competitively bind to miR-92a-3p and regulate FBXW7 expression. Our study provided new insight into the post-transcriptional regulation mechanism of lncRNA MT1JP, and suggested that MT1JP may act as a potential therapeutic target and prognosis biomarker for GC.


Subject(s)
F-Box-WD Repeat-Containing Protein 7/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Stomach Neoplasms/pathology , Animals , Cell Movement , Cell Proliferation , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Humans , Lymphatic Metastasis , Mice , Neoplasm Staging , Neoplasm Transplantation , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain Reaction , Stomach Neoplasms/genetics
13.
Int J Cancer ; 142(9): 1805-1816, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29210057

ABSTRACT

Trefoil Factor 1 (TFF1, also named pS2), which serves as the gastrointestinal mucosal protector, is known as gastric-specific tumor suppressor gene. However, the genetic variants of TFF1 are still not well studied. In our study, we aim to explore the effects of tagging single nucleotide polymorphisms (tagSNPs) of TFF1 on risk and prognosis of gastric cancer. Seven tagSNPs of TFF1 gene were first analyzed in the discovery set, which was consisted of 753 cases and 950 cancer-free controls. Then, the validation set (940 cases and 1,042 controls) was used for further evaluation. Moreover, we also tested the relation between these tagSNPs and prognosis of gastric cancer (GC). A series of experiments were performed to investigate the underlying mechanisms. We found that rs3761376 AA in the promoter region of TFF1, could reduce the expression of TFF1 by affecting the binding affinity of estrogen receptor 1 (ESR1, ERα), and thereby increased the risk of GC (1.29, 1.08-1.53). Moreover, the rs3761376 AA genotype was also found associated with worse prognosis among patients receiving 5-FU based chemotherapy after surgery (1.71, 1.18-2.48). Further functional assays demonstrated that TFF1 could increase the chemosensitivity of 5-FU by modulating NF-κB targeted genes. These results identified the effect of rs3761376 on TFF1 expression, which accounted for the correlation with susceptibility and prognosis of GC; and this genetic variant may be a potential biomarker to predict the risk and survival of GC.


Subject(s)
Stomach Neoplasms/genetics , Trefoil Factor-1/genetics , Aged , Case-Control Studies , Estrogen Receptor alpha/biosynthesis , Estrogen Receptor alpha/genetics , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Neoplasm Staging , Polymorphism, Single Nucleotide , Prognosis , Promoter Regions, Genetic , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Trefoil Factor-1/biosynthesis
14.
Environ Microbiol ; 20(3): 1095-1111, 2018 03.
Article in English | MEDLINE | ID: mdl-29349913

ABSTRACT

Over the span of a year, we investigated the interactions between biotic and abiotic factors within the eutrophic Neuse River Estuary (NRE). Through metatranscriptomic sequencing in combination with water quality measurements, we show that there are different metabolic strategies deployed along the NRE. In the upper estuary, taxonomically resolved phytoplankton groups express more transcripts of genes for synthesis of cellular components and carbon metabolism whereas in the lower estuary, transcripts allocated to nutrient metabolism and transport were more highly expressed. Metabolisms for polysaccharide synthesis and transportation were elevated in the lower estuary and could be reflective of unbalanced growth and/or interactions with their surrounding microbial consortia. Our results indicate phytoplankton have high metabolic activity, suggestive of increased growth rates in the upper estuary and display patterns reflective of nutrient limitation in the lower estuary. Among all the environmental parameters varying along the NRE, nitrogen availability is found to be the main driving factor for the observed spatial divergence.


Subject(s)
Environmental Monitoring , Eutrophication/physiology , Gene Expression Regulation/genetics , Phytoplankton/growth & development , Phytoplankton/metabolism , Estuaries , Eukaryota/growth & development , Gene Expression Profiling , Microbial Consortia/physiology , Nitrogen/analysis , Phytoplankton/genetics , Rivers/chemistry , Rivers/microbiology , Seasons
15.
Environ Microbiol ; 20(8): 3109-3126, 2018 08.
Article in English | MEDLINE | ID: mdl-30117243

ABSTRACT

Diatoms are a highly successful group of photosynthetic protists that often thrive under adverse environmental conditions. Members of the genus Pseudo-nitzschia are ecologically important diatoms which are able to subsist during periods of chronic iron limitation and form dense blooms following iron fertilization events. The cellular strategies within diatoms that orchestrate these physiological responses to variable iron concentrations remain largely uncharacterized. Using a combined transcriptomic and proteomic approach, we explore the exceptional ability of a diatom isolated from the iron-limited Northeast Pacific Ocean to reorganize its intracellular processes as a function of iron. We compared the molecular responses of Pseudo-nitzschia granii observed under iron-replete and iron-limited growth conditions to those of other model diatoms. Iron-coordinated molecular responses demonstrated some agreement between gene expression and protein abundance, including iron-starvation-induced-proteins, a putative iron transport system and components of photosynthesis and the Calvin cycle. Pseudo-nitzschia granii distinctly differentially expresses genes encoding proteins involved in iron-independent photosynthetic electron transport, urea acquisition and vitamin synthesis. We show that P. granii is unique among studied diatoms in its physiology stemming from distinct cellular responses, which may underlie its ability to subsist in low iron regions and rapidly bloom to outcompete other diatom taxa following iron enrichment.


Subject(s)
Diatoms/genetics , Diatoms/metabolism , Iron/metabolism , Diatoms/classification , Diatoms/isolation & purification , Electron Transport , Pacific Ocean , Photosynthesis , Proteomics , Transcriptome
16.
Cell Physiol Biochem ; 48(6): 2247-2257, 2018.
Article in English | MEDLINE | ID: mdl-30114685

ABSTRACT

BACKGROUND/AIMS: Imbalance of oxidative/antioxidative enzymes in cells is associated with carcinogenesis and cancer cell chemoresistance. The aim of this study was to examine the clinical significance of potentially functional single nucleotides polymorphisms (SNPs) in antioxidative enzymes, GPxs and CAT, in stages II and III gastric cancer patients. METHODS: A total of 591 gastric cancer patients who had radical gastrectomy were recruited. 207 patients received platinum and fluorouracil-based (PF-based) adjuvant chemotherapy and 384 patients were untreated. GPx1 rs1050450, GPx2 rs4902346, GPx3 rs736775, rs3828599 and CAT rs769218 were genotyped in the DNA samples extracted from paraffin-embedded tumor tissue. RESULTS: CAT rs769218 was significantly correlated with the overall survival (OS) in the dominant model (P = 0.014). Multivariate analysis revealed that CAT rs769218 GA/AA (HR, 0.715; 95%CI, 0.562-0.910, P = 0.006) was an independent prognostic marker indicating improved survival. After adjustments, GPx3 rs736775 TC/CC was significantly associated with improved OS (HR, 0.621; 95%CI, 0.399-0.965; P=0.034) in patients treated with PF-based adjuvant chemotherapy, and CAT rs769218 GA/AA was significantly associated with improved OS (HR, 0.646; 95% CI, 0.482-0.864; P = 0.003) in the untreated patients. PF-based chemotherapy significantly decreased risk of death for patients carrying GPx3 rs736775 TC/CC and age ≤ 60 years or with diffused type adenocarcinoma compared to surgery alone. CONCLUSION: our findings suggested CAT rs769218 and GPx3 rs736775 may be considered as prognostic markers in gastric cancer. Patient stratification by GPx3 rs736775 and conventional pathological parameters may provide additional predictive information in treatment decision-making.


Subject(s)
Catalase/genetics , Fluorouracil/therapeutic use , Glutathione Peroxidase/genetics , Platinum Compounds/therapeutic use , Stomach Neoplasms/drug therapy , Alleles , Chemotherapy, Adjuvant , Female , Genotype , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Polymorphism, Single Nucleotide , Prognosis , Proportional Hazards Models , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Glutathione Peroxidase GPX1
17.
Mol Cancer ; 16(1): 46, 2017 02 23.
Article in English | MEDLINE | ID: mdl-28231797

ABSTRACT

BACKGROUND: Inactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. It is necessary to uncover the detailed pattern of whole genome-wide abnormal DNA methylation during the development of gastric cancer (GC). METHOD: We performed a genome-wide methylation detection using 12 paired of GC tissues and their corresponding normal tissues. Methylation-specific PCR (MSP) and bisulphite sequencing (BSP) were used to measure methylation status of specific CpG site. Based on the bioinformatic analysis, the cell phenotypes and mouse model experiments were constructed to detect effect of the target gene. Using the Kaplan-Meier survival curve, the clinical value of KCNMA1 was assessed in GC patients. RESULTS: The CpG site cg24113782 located at the promoter of KCNMA1 showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation of KCNMA1 was detected in 68.7% (77/112) of tumor tissues, compared with 16.2% (18/112) of normal tissues (P < 0.001). The survival curve indicated that KCNMA1 hypermethylation was significantly associated with the shortened survival in GC patients (P = 0.036). KCNMA1 significantly inhibited biological malignant behavior of gastric cancer cell by inducing cell apoptosis in vitro, and suppressed xenograft tumor growth in subcutaneous mouse models (both P < 0.001). Furthermore, the anti-tumor effect of KCNMA1was mediated through suppressing the expression of PTK2. CONCLUSION: KCNMA1 is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer.


Subject(s)
Focal Adhesion Kinase 1/genetics , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Whole Genome Sequencing/methods , Aged , Animals , Cell Line, Tumor , DNA Methylation , Epigenesis, Genetic , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Middle Aged , Neoplasm Transplantation , Prognosis , Promoter Regions, Genetic , Signal Transduction , Survival Analysis
18.
J Gastroenterol Hepatol ; 32(4): 819-827, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27529338

ABSTRACT

BACKGROUND AND AIM: In our previous study, we demonstrated that four microRNAs (miRNAs) (miR-26a, miR-142-3p, miR-148a, and miR-195) that were downregulated in both plasma and tumor tissues were confirmed to be promising non-invasive diagnostic biomarkers for gastric cancer (GC). METHODS: We used the quantitative reverse transcription polymerase chain reaction to assess the expression levels of the four miRNAs from paraffin-embedded surgical specimens of GC patients. Kaplan-Meier curves and log-rank test were applied to predict the correlation between miRNAs and cumulative overall survival (OS) of patients with GC. Besides, we performed in vitro assays including cell proliferation, migration, invasion and colony formation, and apoptosis. RESULTS: The median of miRNA expression in paraffin-embedded tissues were used as the cutoff value to classify patients into high or low expression groups. Down-regulation of miR-26a and miR-148a was significantly associated with shorter OS of GC patients either in the test set (miR-26a: P = 0.009; miR-148a: P = 0.005) or the validation set (miR-26a: P = 0.011; miR-148a: P = 0.024). When two sets were combined, Cox regression analysis demonstrated that both of miR-26a and miR-148a were independent prognostic factors for predicting OS of patients with GC (miR-26a: HR = 0.76, 95% CI = 0.61-0.94; miR-148a: HR = 0.73, 95% CI = 0.58-0.91). Furthermore, elevated expression of miR-26 significantly suppressed cell proliferation, migration, invasion and colony formation, and induced apoptosis of MGC-803 cells compared with negative control groups (P < 0.05). CONCLUSION: These findings supported miR-26a and miR-148a could serve as potential prognostic biomarkers for GC.


Subject(s)
Biomarkers, Tumor/genetics , Gene Expression , MicroRNAs/genetics , Stomach Neoplasms/genetics , Aged , Apoptosis , Cell Movement , Cell Proliferation , Cells, Cultured , Down-Regulation/genetics , Female , Humans , Male , Middle Aged , Neoplasm Invasiveness , Prognosis , Reverse Transcriptase Polymerase Chain Reaction , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Rate
19.
Mutagenesis ; 31(5): 531-8, 2016 09.
Article in English | MEDLINE | ID: mdl-27091055

ABSTRACT

The long non-coding RNA (lncRNA) H19 as an imprinted gene transcribed from only the maternal allele has the vital role in carcinogenesis. Aberrant H19 expression is involved in bladder cancer development. In this study, we explored the association between single nucleotide polymorphisms (SNPs) in H19 and bladder cancer risk. Four tagging SNPs (tagSNPs) were selected from the 1000 Genomes Project database. In total, 1049 bladder cancer cases and 1399 controls were recruited in this case-control study. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by using unconditional univariate and multivariate logistic regression models to evaluate associations between the H19 tagSNPs genotypes and risk of bladder cancer. We found a statistically significant increased risk of bladder cancer in the carriers of the rs217727 AA genotype compared with carriers of GG/GA genotype (OR = 1.31, 95% CI = 1.03-1.67). The subsequently stratified analyses also revealed that the H19 rs217727 AA genotype remarkably elevated the risk of bladder cancer in subgroups of young subjects (OR = 1.80, 95% CI = 1.16-2.81), males (OR = 1.44, 95% CI = 1.10-1.89) and smokers (OR = 1.55, 95% CI = 1.06-2.27), as well as high tumour grade (OR = 1.89, 95% CI = 1.23-2.91) and invasive disease (OR = 1.62, 95% CI = 1.01-2.60). This finding indicates that the rs217727 polymorphism is significantly associated with the risk of bladder cancer.


Subject(s)
Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics , Urinary Bladder Neoplasms/metabolism , Aged , Asian People/genetics , Case-Control Studies , Female , Humans , Male , Middle Aged , Risk , Urinary Bladder Neoplasms/genetics
20.
Fish Physiol Biochem ; 42(3): 947-54, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26719066

ABSTRACT

In vertebrates, the aromatase coded by the cyp19a1a gene can catalyze the conversion from androgens to estrogens. Thus, the regulatory mechanisms of cyp19a1a gene expression are a critical research field in reproductive endocrinology. In this study, we use zebrafish as a model to study the dynamic methylation levels of the cyp19a1a gene core promoter during zebrafish ovarian folliculogenesis. The results show that there is an apparent fluctuation of the methylation levels of zebrafish cyp19a1a core promoter. Moreover, the methylation levels are inversely correlated with the expression levels of cyp19a1a transcripts when the ovarian follicles develop from PV into the MV stage. Also, the CpG dinucleotides which are close to the transcriptional starting site may have provided a significant blocking effect on inhibiting the transcriptional function of RNA polymerase II. Taken together, the results from the present study strongly suggest that DNA methylation was one of mechanisms that are involved in the regulation of cyp19a1a gene expression during folliculogenesis. This methylation mechanism modifying transcriptional process accompanied with zebrafish ovarian folliculogenesis might also shed new light on the regulation of cyp19a1a expression during the ovarian developmental stage in other vertebrates.


Subject(s)
Aromatase/genetics , DNA Methylation , Ovarian Follicle/metabolism , Zebrafish Proteins/genetics , Zebrafish/genetics , Animals , Female , Ovarian Follicle/growth & development , Promoter Regions, Genetic , RNA, Messenger/metabolism , Zebrafish/growth & development
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