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1.
Nucleic Acids Res ; 2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32459350

RESUMO

Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we discover an HRP2-DPF3a-BAF epigenetic pathway that coordinates methylated histone H3 lysine 36 (H3K36me) and ATP-dependent chromatin remodeling to regulate chromatin dynamics and gene transcription during myogenic differentiation. Using siRNA screening targeting epigenetic modifiers, we identify hepatoma-derived growth factor-related protein 2 (HRP2) as a key regulator of myogenesis. Knockout of HRP2 in mice leads to impaired muscle regeneration. Mechanistically, through its HIV integrase binding domain (IBD), HRP2 associates with the BRG1/BRM-associated factor (BAF) chromatin remodeling complex by interacting directly with the BAF45c (DPF3a) subunit. Through its Pro-Trp-Trp-Pro (PWWP) domain, HRP2 preferentially binds to H3K36me2. Consistent with the biochemical studies, ChIP-seq analyses show that HRP2 colocalizes with DPF3a across the genome and that the recruitment of HRP2/DPF3a to chromatin is dependent on H3K36me2. Integrative transcriptomic and cistromic analyses, coupled with ATAC-seq, reveal that HRP2 and DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of BRG1, the ATPase subunit of the BAF complex. Taken together, these results illuminate a key role for the HRP2-DPF3a-BAF complex in the epigenetic coordination of gene transcription during myogenic differentiation.

2.
Biochem Biophys Res Commun ; 520(3): 544-550, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31615655

RESUMO

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC.

3.
Thyroid ; 29(6): 809-823, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924726

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with no effective treatment currently available. The molecular mechanisms of ATC carcinogenesis remain poorly understood. The objective of this study was to investigate the mechanisms and functions of super-enhancer (SE)-driven oncogenic transcriptional addiction in the progression of ATC and identify new drug targets for ATC treatments. Methods: High-throughput chemical screening was performed to identify new drugs inhibiting ATC cell growth. Cell viability assay, colony formation analysis, cell-cycle analysis, and animal study were used to examine the effects of drug treatments on ATC progression. Chromatin immunoprecipitation sequencing was conducted to establish a SE landscape of ATC. Integrative analysis of RNA sequencing, chromatin immunoprecipitation sequencing, and CRISPR/Cas9-mediated gene editing was used to identify THZ1 target genes. Drug combination analysis was performed to assess drug synergy. Patient samples were analyzed to evaluate candidate biomarkers of prognosis in ATC. Results: THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), was identified as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid carcinoma cells, are exceptionally sensitive to CDK7 inhibition. An integrative analysis of both gene expression profiles and SE features revealed that the SE-mediated oncogenic transcriptional amplification mediates the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays led to the discovery of a number of novel cancer genes of ATC, including PPP1R15A, SMG9, and KLF2. Inhibition of PPP1R15A with Guanabenz or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, CDK7 or PPP1R15A inhibition sensitizes ATC cells to conventional chemotherapy. Conclusions: Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.

4.
Oncol Lett ; 15(4): 4767-4774, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29552116

RESUMO

Malignant melanoma is characterized by rapid deterioration, early metastasis and high mortality. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1), which catalyzes 2-methylthio (ms2) modification of mitochondrial transfer RNAs, has been reported to induce cancer cell apoptosis, by a phospho-c-Jun N-terminal kinase (p-JNK) signaling pathway. The present study was the first to report on the association between CDK5RAP1 deficiency and nuclear factor-κB (NF-κB) signaling pathway during the apoptosis process in human malignant melanoma (A375) cells. CDK5RAP1 small interfering RNA (siRNA) and control siRNA were transfected into A375 cells. CDK5RAP1 deficiency inhibited Ca2+ influx in A375 cells. CDK5RAP1 deficiency also suppressed the proliferation of A375 cells, induced A375 cells apoptosis, and increased the generation of reactive oxygen species (ROS). In addition, CDK5RAP1 deficiency induced the phosphorylation of NF-κB and Bcl-2/Bcl-xl-associated death promoter (Bad). Notably, the phosphorylation of B-cell lymphoma-xl (Bcl-xl) and B-cell lymphoma-2 (Bcl-2) was downregulated by CDK5RAP1 deficiency. Pretreatment with pyrrolidine dithiocarbamate (PDTC), the inhibitor of NF-κB, prevented the decrease in cell proliferation and apoptosis induced by CDK5RAP1 deficiency in A375 cells. However, pretreatment with PDTC did not affect the generation of ROS in A375 cells, indicating that ROS is an upstream target of NF-κB signaling pathway during the apoptosis process. Taken together, CDK5RAP1 deficiency induces cell apoptosis in malignant melanoma A375 cells via the NF-κB signaling pathway. The results from the present study indicated a potential novel candidate for the treatment of skin cancer.

5.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 33(6): 550-554, 2017 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-29931907

RESUMO

OBJECTIVE: To study the effects of Chai Qin Cheng Qi Decoction(CQCQD)(Traditional Chinese Medicine)on severe acute pancreatitis (SAP)complicated liver damage in rats. METHODS: Seventy-two SD rats were randomly divided into three groups(n=24):Sham group, SAP group and CQCQD treatment group. SAP model was induced by retrograde injection with sodium taurocholate. The rats in CQCQD group received treatment with CQCQD. After modeling 1 h, 5 h, 10 h, pancreas and liver histopathological changes were observed. The serum levels of interleukin-6(IL-6), amylase(AMS), alanine aminotransferase(ALT) and aspartate transaminase(AST) were detected. IL-6 and monocyte chemotactic protein 1(MCP-1)mRNA in pancreas and liver were assayed. RESULTS: Compared with sham group, the activities of AMS,ALT and AST and the serum level of IL-6 in SAP group were increased significantly. The levels of MCP-1 and IL-6 mRNA in pancreas and liver tissue were increased (P<0.05). Compared with SAP group, the activities of AMS,ALT and AST and the level of IL-6 in CQCQD group were reduced significantly (P<0.05). The pancreas and liver tissue pathological damage alleviated. The levels of IL-6 and MCP-1mRNA in pancreas and liver were decreased significantly(P<0.05). CONCLUSIONS: MCP-1 takes part in the progression of SAP complicated liver damage; CQCQD can significantly inhibit the expression of pancreas and liver MCP-1, alleviate pathological damage of pancreas and liver in SAP and play a therapeutic role in SAP complicated liver damage.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Doença Aguda , Alanina Transaminase/sangue , Amilases/sangue , Animais , Aspartato Aminotransferases/sangue , Quimiocina CCL2/metabolismo , Interleucina-6/sangue , Fígado/patologia , Hepatopatias/etiologia , Pancreatite/complicações , Ratos , Ratos Sprague-Dawley
6.
Oncol Rep ; 34(3): 1478-86, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26133107

RESUMO

Skin cancer is one of the most common types of malignancy in the world. UV radiation is known as the primary environmental carcinogen responsible for skin cancer development. However, UV radiation is a ubiquitous substance existing in the environment and the physiological effect of UV radiation is consistently ignored. Therefore, in the present study, the physiological effect of UV radiation on inhibition of skin cancer was investigated. Normal mouse skin was processing by no pre-radiation or pre-radiation of low-dose UV before a medium or high dose of UV radiation. We found that the low-dose pre-radiated mouse skin tissue exhibited low skin inflammation, skin ROS production and consequently low skin epithelial hyperplasia after the medium-dose UV radiation compared with the no pre-radiated mouse. However, this inhibition was not indicated in the high-dose UV radiation group after low-dose pre-radiation. Furthermore, western blot analysis and gelatin zymography showed low expression and activation of MMP2 in the skin tissues processed following medium-dose radiation, but not in tissues treated with high-dose radiation after a low-dose pre-radiation. Further investigation of MMP2 inhibitors of TIMP2/TIMP4 showed an upregulated TIMP2 expression, but not TIMP4. Collectively, these data indicate that low-dose pre-radiation attenuates the skin inflammation and ROS production induced by medium-dose UV radiation and also elevates TIMP2 to withstand MMP2, therefore suppressing skin hyperplasia. The present study indicates a novel concept or prophylactic function of moderate UV radiation as a preventative strategy.


Assuntos
Metaloproteinase 2 da Matriz/biossíntese , Neoplasias Cutâneas/patologia , Pele/efeitos da radiação , Inibidor Tecidual de Metaloproteinase-2/biossíntese , Animais , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Hiperplasia/patologia , Metaloproteinase 2 da Matriz/genética , Camundongos , Doses de Radiação , Espécies Reativas de Oxigênio/metabolismo , Pele/patologia , Neoplasias Cutâneas/radioterapia , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidores Teciduais de Metaloproteinases/biossíntese , Inibidores Teciduais de Metaloproteinases/genética , Raios Ultravioleta/efeitos adversos
7.
Mol Med Rep ; 11(6): 4183-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25650554

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a genetic background. The C5a­receptor (C5aR) pathway has been reported to be involved in AD; however, the precise pathogenesis remains to be elucidated. In the present study, the contribution of the C5aR pathway to AD in mice was investigated. A BALB/c mouse model of AD was induced by application of 2,4­dinitrochlorobenzene (DNCB) onto hairless dorsal skin. Following DNCB application for 2 weeks, C5aR expression in skin tissue was assessed by reverse transcription quantitative polymerase chain reaction. C5aR expression in skin tissue was significantly increased in mice with AD. In an additional experiment, C5aR antagonist (C5aRA) intracutaneously injected in combination with DNCB treatment. The skin­fold thickness, number of total infiltrating leukocytes and mast cells infiltrating in skin tissue were measured. Interleukin­4 (IL­4) and interferon­Î³ (IFN­Î³) levels in skin tissue and IL­4, IFN­Î³, histamine and immunoglobulin E (IgE) levels in serum were measured using ELISA. The skin­fold thickness, numbers of total infiltrating leukocytes and mast cells in skin tissue, as well as levels of IL­4, IFN­Î³, histamine and IgE were significantly increased in mice with AD. However, simultaneous treatment with C5aRA significantly attenuated increases in skin fold thickness and the numbers of total infiltrating leukocytes and mast cells in skin tissue. Treatment with C5aRA also decreased IL­4 and IFN­Î³ levels in skin tissue, as well as the levels of IL­4, IFN­Î³, histamine and IgE in the serum. In conclusion, C5aRA inhibited AD in mice, possibly through suppression of the C5aR­mediated cascade action of mast cells.


Assuntos
Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Transdução de Sinais , Animais , Complemento C5a/imunologia , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dinitroclorobenzeno/efeitos adversos , Modelos Animais de Doenças , Expressão Gênica , Histamina/sangue , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interferon gama/sangue , Interferon gama/metabolismo , Interleucina-4/sangue , Interleucina-4/metabolismo , Masculino , Camundongos , Infiltração de Neutrófilos , Receptor da Anafilatoxina C5a/genética
8.
J Eukaryot Microbiol ; 62(4): 470-80, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25523905

RESUMO

We investigated the toxicity of Karenia mikimotoi toward three model grazers, the cladoceran Moina mongolica, the copepod Pseudodiaptomus annandalei, and the crustacean Artemia salina, and explored its chemical response upon zooplankton grazing. An induction experiment, where K. mikimotoi was exposed to grazers or waterborne cues from the mixed cultures revealed that K. mikimotoi might be toxic or nutritionally inadequate toward the three grazers. In general, direct exposure to the three grazers induced the production of hemolytic toxins and the synthesis of eicosapentaenoic acid (EPA). Both EPA and the hemolytic toxins from K. mikimotoi decreased the survival rate of the three grazers. In addition, the survival rates of M. mongolica, P. annandalei, and A. salina in the presence of induced K. mikimotoi that had previously been exposed to a certain grazer were lower than their counterparts caused by fresh K. mikimotoi, suggesting that exposure to some grazers might increase the toxicity of K. mikimotoi. The chemical response and associated increased resistance to further grazing suggested that K. mikimotoi could produce deterrents to protect against grazing by zooplankton and that the substances responsible might be hemolytic toxins and EPA.


Assuntos
Dinoflagelados/química , Dinoflagelados/fisiologia , Zooplâncton/fisiologia , Animais , Artemia/crescimento & desenvolvimento , Artemia/fisiologia , Cladóceros/crescimento & desenvolvimento , Cladóceros/fisiologia , Ácido Eicosapentaenoico/biossíntese , Comportamento Alimentar , Herbivoria , Toxinas Marinhas/toxicidade , Zooplâncton/crescimento & desenvolvimento
9.
Biochim Biophys Acta ; 1841(12): 1709-15, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25240836

RESUMO

Psoriasis is a chronic inflammatory skin disease, which has been linked to dyslipidemia with potential functional impairment of lipoproteins. This cross-sectional study was designed to characterize the biological activities of plasma lipoproteins in 25 patients with psoriasis and 25 age- and sex-matched healthy controls. In the present study, we found that plasma levels of high-density lipoprotein (HDL) cholesterol were decreased in the psoriasis group compared to healthy controls. The malondialdehyde (MDA) content in plasma, in HDL3 and in low-density lipoprotein (LDL) were increased. However, the activity of plasma paraoxonase-1 (PON-1) decreased in psoriasis and negatively correlated with the psoriasis area and severity index (PASI). Moreover, plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were increased in psoriasis and positively correlated with the PASI. High-sensitivity C-reactive protein (hs-CRP) was increased in psoriasis, but did not reach significance when correlated with PASI. In vitro tests displayed that the functionalities of HDL3 isolated from psoriatic patients significantly decreased, which were assessed in four independent ways, namely (1) protection against LDL oxidation, (2) inhibition of tumor necrosis factor-α (TNF-α) induced monocyte adherence to endothelial cells, (3) prevention of oxidized low density lipoprotein (ox-LDL) induced monocyte migration, and (4) protection of endothelial cells from TNF-α induced apoptosis. Further, pro-oxidative and pro-inflammatory properties of LDL isolated from psoriatic patients were increased. In conclusion, the biological activities of psoriatic lipoproteins are impaired in both HDL and LDL which may provide a link between psoriasis and cardiovas- cular disease.


Assuntos
Inflamação/patologia , Lipoproteínas HDL/metabolismo , Psoríase/patologia , Adulto , Biomarcadores/sangue , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Oxirredução , Psoríase/sangue
10.
Nat Genet ; 46(1): 45-50, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24212883

RESUMO

To explore the contribution of functional coding variants to psoriasis, we analyzed nonsynonymous single-nucleotide variants (SNVs) across the genome by exome sequencing in 781 psoriasis cases and 676 controls and through follow-up validation in 1,326 candidate genes by targeted sequencing in 9,946 psoriasis cases and 9,906 controls from the Chinese population. We discovered two independent missense SNVs in IL23R and GJB2 of low frequency and five common missense SNVs in LCE3D, ERAP1, CARD14 and ZNF816A associated with psoriasis at genome-wide significance. Rare missense SNVs in FUT2 and TARBP1 were also observed with suggestive evidence of association. Single-variant and gene-based association analyses of nonsynonymous SNVs did not identify newly associated genes for psoriasis in the regions subjected to targeted resequencing. This suggests that coding variants in the 1,326 targeted genes contribute only a limited fraction of the overall genetic risk for psoriasis.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Adulto , Aminopeptidases/genética , Grupo com Ancestrais do Continente Asiático/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Estudos de Casos e Controles , Conexina 26 , Conexinas/genética , Feminino , Fucosiltransferases/genética , Estudo de Associação Genômica Ampla , Guanilato Ciclase/genética , Haplótipos , Humanos , Masculino , Proteínas de Membrana/genética , Antígenos de Histocompatibilidade Menor , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genética , Receptores de Interleucina/genética , Adulto Jovem
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