Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 50
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
DNA Repair (Amst) ; 107: 103183, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34419698

RESUMO

Our nuclear genomes are complexed with histone proteins to form nucleosomes, the repeating units of chromatin which function to package and limit unscheduled access to the genome. In response to helix-distorting DNA lesions and DNA double-strand breaks, chromatin is disassembled around the DNA lesion to facilitate DNA repair and it is reassembled after repair is complete to reestablish the epigenetic landscape and regulating access to the genome. DNA damage also triggers decondensation of the local chromatin structure, incorporation of histone variants and dramatic transient increases in chromatin mobility to facilitate the homology search during homologous recombination. Here we review the current state of knowledge of these changes in histone and chromatin dynamics in response to DNA damage, the molecular mechanisms mediating these dynamics, as well as their functional contributions to the maintenance of genome integrity to prevent human diseases including cancer.

2.
FASEB J ; 35(9): e21814, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369624

RESUMO

Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin-responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non-histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes. Among these, the p53-responsive carbohydrate metabolic genes Tp53-induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose-mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA-Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53-mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Mitocôndrias/genética , Chaperonas Moleculares/genética , Monoéster Fosfórico Hidrolases/genética , Fatores de Transcrição/genética , Transcrição Genética/genética , Proteína Supressora de Tumor p53/genética , Adaptação Biológica/genética , Apoptose/genética , Linhagem Celular Tumoral , Metabolismo Energético/genética , Glucose/genética , Células Hep G2 , Homeostase/genética , Humanos , Potencial da Membrana Mitocondrial/genética , Estresse Fisiológico/genética , Ativação Transcricional/genética
3.
PLoS Negl Trop Dis ; 15(8): e0009101, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34370731

RESUMO

BACKGROUND: In 2005, Bangladesh, India and Nepal agreed to eliminate visceral leishmaniasis (VL) as a public health problem. The approach to this was through improved case detection and treatment, and controlling transmission by the sand fly vector Phlebotomus argentipes, with indoor residual spraying (IRS) of insecticide. Initially, India applied DDT with stirrup pumps for IRS, however, this did not reduce transmission. After 2015 onwards, the pyrethroid alpha-cypermethrin was applied with compression pumps, and entomological surveillance was initiated in 2016. METHODS: Eight sentinel sites were established in the Indian states of Bihar, Jharkhand and West Bengal. IRS coverage was monitored by household survey, quality of insecticide application was measured by HPLC, presence and abundance of the VL vector was monitored by CDC light traps, insecticide resistance was measured with WHO diagnostic assays and case incidence was determined from the VL case register KAMIS. RESULTS: Complete treatment of houses with IRS increased across all sites from 57% in 2016 to 70% of houses in 2019, rising to >80% if partial house IRS coverage is included (except West Bengal). The quality of insecticide application has improved compared to previous studies, average doses of insecticide on filters papers ranged from 1.52 times the target dose of 25mg/m2 alpha-cypermethrin in 2019 to 1.67 times in 2018. Resistance to DDT has continued to increase, but the vector was not resistant to carbamates, organophosphates or pyrethroids. The annual and seasonal abundance of P. argentipes declined between 2016 to 2019 with an overall infection rate of 0.03%. This was associated with a decline in VL incidence for the blocks represented by the sentinel sites from 1.16 per 10,000 population in 2016 to 0.51 per 10,000 in 2019. CONCLUSION: Through effective case detection and management reducing the infection reservoirs for P. argentipes in the human population combined with IRS keeping P. argentipes abundance and infectivity low has reduced VL transmission. This combination of effective case management and vector control has now brought India within reach of the VL elimination targets.

4.
Cancer Res ; 81(16): 4174-4182, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34016622

RESUMO

Despite extensive progress in developing anticancer therapies, therapy resistance remains a major challenge that promotes disease relapse. The changes that lead to therapy resistance can be intrinsically present or may be initiated during treatment. Genetic and epigenetic heterogeneity in tumors make it more challenging to deal with therapy resistance. Recent advances in genome-wide analyses have revealed that the deregulation of distal gene regulatory elements, such as enhancers, appears in several pathophysiological conditions, including cancer. Beyond the conventional function of enhancers in recruiting transcription factors to gene promoters, enhancer elements are also transcribed into noncoding RNAs known as enhancer RNAs (eRNA). Accumulating evidence suggests that uncontrolled enhancer activity with aberrant eRNA expression promotes oncogenesis. Interestingly, tissue-specific, transcribed eRNAs from active enhancers can serve as potential therapeutic targets or biomarkers in several cancer types. This review provides a comprehensive overview of the mechanisms of enhancer transcription and eRNAs as well as their potential roles in cancer and drug resistance.

5.
Biochem J ; 478(5): 1117-1136, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33501928

RESUMO

Asf1 is a highly conserved histone chaperone that regulates tightly coupled nucleosome assembly/disassembly process. We observed that Plasmodium falciparum Asf1 (PfAsf1) is ubiquitously expressed in different stages of the life cycle of the parasite. To gain further insight into its biological activity, we solved the structure of N-terminal histone chaperone domain of PfAsf1 (1-159 amino acids) by X-ray crystallography to a resolution of 2.4 Å. The structure is composed of two beta-sheet to form a beta-sandwich, which resembles an immunoglobulin-like fold. The surface-charge distribution of PfAsf1 is distinct from yAsf1 and hAsf1 although the core-structure shows significant similarity. The crystal-structure indicated that PfAsf1 may exist in a dimeric-state which was further confirmed by solution cross-linking experiment. PfAsf1 was found to specifically interact with Plasmodium histone H3 and H4 and was able to deposit H3/H4 dimer onto DNA-template to form disomes, showing its characteristic histone chaperone activity. We mapped the critical residues of PfAsf1 involved in histone H3/H4 interaction and confirmed by site-directed mutagenesis. Further analysis indicates that histone interacting surface of Asf1 is highly conserved while the dimerization interface is variable. Our results identify the role of PfAsf1 as a mediator of chromatin assembly in Plasmodium falciparum, which is the causative agent of malignant malaria in humans.


Assuntos
Montagem e Desmontagem da Cromatina , Replicação do DNA , Chaperonas de Histonas/química , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Plasmodium falciparum/metabolismo , Sequência de Aminoácidos , Cristalografia por Raios X , Eritrócitos/parasitologia , Evolução Molecular , Histonas/química , Humanos , Modelos Moleculares , Filogenia , Conformação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Homologia de Sequência
6.
Mol Biol Rep ; 48(1): 897-914, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33400075

RESUMO

Enhanced metastasis and disease recurrence accounts for the high mortality rates associated with cancer. The process of Epithelial-Mesenchymal Transition (EMT) contributes towards the augmentation of cancer invasiveness along with the gain of stem-like and the subsequent drug-resistant behavior. Apart from the well-established transcriptional regulation, EMT is also controlled post-transcriptionally by virtue of alternative splicing (AS). Numerous genes including Fibroblast Growth Factor receptor (FGFR) as well as CD44 are differentially spliced during this trans-differentiation process which, in turn, governs cancer progression. These splicing alterations are controlled by various splicing factors including ESRP, RBFOX2 as well as hnRNPs. Here, we have depicted the mechanisms governing the splice isoform switching of FGFR and CD44. Moreover, the role of the splice variants generated by AS of these gene transcripts in modulating the metastatic potential and stem-like/chemoresistant behavior of cancer cells has also been highlighted. Additionally, the involvement of splicing factors in regulating EMT/invasiveness along with drug-resistance as well as the metabolic properties of the cells has been emphasized. Tumorigenesis is accompanied by a remodeling of the cellular splicing profile generating diverse protein isoforms which, in turn, control the cancer-associated hallmarks. Therefore, we have also briefly discussed about a wide variety of genes which are differentially spliced in the tumor cells and promote cancer progression. We have also outlined different strategies for targeting the tumor-associated splicing events which have shown promising results and therefore this approach might be useful in developing therapies to reduce cancer aggressiveness in a more specific manner.


Assuntos
Carcinogênese/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Receptores de Hialuronatos/genética , Recidiva Local de Neoplasia/genética , Neoplasias/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Processamento Alternativo , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Metástase Linfática , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
7.
Cell Death Dis ; 11(12): 1073, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323928

RESUMO

The major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.


Assuntos
Oncogenes , Proteínas Supressoras de Tumor/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genoma Humano , Histona Desmetilases/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
8.
Biochem J ; 477(19): 3803-3818, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-32926159

RESUMO

hTERT, the catalytic component of the human telomerase enzyme, is regulated by post-translational modifications, like phosphorylation and ubiquitination by multiple proteins which remarkably affects the overall activity of the enzyme. Here we report that hTERT gets SUMOylated by SUMO1 and polycomb protein CBX4 acts as the SUMO E3 ligase of hTERT. hTERT SUMOylation positively regulates its telomerase activity which can be inhibited by SENP3-mediated deSUMOylation. Interestingly, we have established a new role of hTERT SUMOylation in the repression of E-cadherin gene expression and consequent triggering on the epithelial-mesenchymal-transition (EMT) program in breast cancer cells. We also observed that catalytically active CBX4, leads to retention of hTERT/ZEB1 complex onto E-cadherin promoter leading to its repression through hTERT-SUMOylation. Further through wound healing and invasion assays in breast cancer cells, we showed the tumor promoting ability of hTERT was significantly compromised upon overexpression of SUMO-defective mutant of hTERT. Thus our findings establish a new post-translational modification of hTERT which on one hand is involved in telomerase activity maintenance and on the other hand plays a crucial role in the regulation of gene expression thereby promoting migration and invasion of breast cancer cells.


Assuntos
Antígenos CD/metabolismo , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Movimento Celular , Ligases/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Telomerase/metabolismo , Transcrição Genética , Antígenos CD/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Feminino , Células HeLa , Humanos , Ligases/genética , Células MCF-7 , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteínas do Grupo Polycomb/genética , Telomerase/genética
9.
F1000Res ; 9: 493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32676186

RESUMO

Background: Medicinal plants are a source of phytochemicals and they are used for the treatment of several oxidative stress-related or other diseases for their effectiveness, low toxicity and easy availability. Five traditionally used and less characterized herbaceous weeds of West Bengal, India, namely, Heliotropium indicum, Tridax procumbens, Cleome rutidosperma, Commelina benghalensis and Euphorbia hirta, were investigated for the current research study. Methods: Aqueous and 70% ethanolic extracts of the leaves were analyzed for estimation of essential phytochemicals and to evaluate their in vitro antioxidant status, medicinal properties and cytotoxic effects. To the best of our knowledge, several assays and comparative evaluations using these herbs are reported for the first time. For quantitative study, UV-vis spectrophotometry and high-performance liquid chromatography with diode array detector HPLC-DAD techniques were used. Antibacterial properties were investigated using the Kirby-Bauer disc diffusion method. For in vitro anti-lithiatic study, a titration method was used. The cell viability assay was done using peripheral blood mononuclear cells. Results: The aqueous extract exhibits higher content of polyphenols, flavonoids, tannins and inhibition percentage values for free radical scavenging assays, whereas the 70% ethanolic extract exhibits higher content of alkaloids and cardiac glycosides. HPLC-DAD analysis of 70% ethanolic extracts led us to identify 10 predominant phenolic constituents. Euphorbia hirta extracts showed minimum cytotoxicity (cell death ~2.5% and 4 % in water and 70% ethanolic extract, respectively ), whereas Cleome rutidosperma and Tridax procumbens' 70% ethanolic extracts showed higher cell death (~13% and 28%, respectively), compared with the control (cell death ~10-12%). Conclusions: The study concluded that of all the medicinal weeds selected for the current study, Euphorbia hirta possesses the highest amount of bioactive compounds and hence exhibits the highest in vitro antioxidant activity and promising in vitro medicinal properties.


Assuntos
Antioxidantes/farmacologia , Extratos Vegetais/farmacologia , Plantas Daninhas/química , Asteraceae/química , Células Cultivadas , Cleome/química , Commelina/química , Euphorbia/química , Heliotropium/química , Humanos , Índia , Leucócitos Mononucleares/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia
10.
Int J Mol Sci ; 21(10)2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32466143

RESUMO

Genome-wide RNA sequencing has shown that only a small fraction of the human genome is transcribed into protein-coding mRNAs. While once thought to be "junk" DNA, recent findings indicate that the rest of the genome encodes many types of non-coding RNA molecules with a myriad of functions still being determined. Among the non-coding RNAs, long non-coding RNAs (lncRNA) and enhancer RNAs (eRNA) are found to be most copious. While their exact biological functions and mechanisms of action are currently unknown, technologies such as next-generation RNA sequencing (RNA-seq) and global nuclear run-on sequencing (GRO-seq) have begun deciphering their expression patterns and biological significance. In addition to their identification, it has been shown that the expression of long non-coding RNAs and enhancer RNAs can vary due to spatial, temporal, developmental, or hormonal variations. In this review, we explore newly reported information on estrogen-regulated eRNAs and lncRNAs and their associated biological functions to help outline their markedly prominent roles in estrogen-dependent signaling.


Assuntos
Elementos Facilitadores Genéticos , Estrogênios/metabolismo , RNA Longo não Codificante/metabolismo , Pequeno RNA não Traduzido/metabolismo , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Longo não Codificante/genética , Pequeno RNA não Traduzido/genética , Ativação Transcricional
11.
Carcinogenesis ; 41(12): 1767-1780, 2020 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-32386317

RESUMO

Previously, our laboratory demonstrated that a deregulated E2F5/p38/SMAD3 axis was associated with uncontrolled cellular proliferation in prostate cancer (PCa). Here, we investigate the role of E2F5 in PCa in further details. RNAi-mediated E2F5 knockdown and pathway-focused gene expression profiling in PC3 cells identified TFPI2 as a downstream target of E2F5. Manipulation of E2F5 expression was also found to alter MMP-2 and MMP-9 levels as detected by Proteome Profiler array, western blot and reverse transcription coupled quantitative polymerase chain reaction Site-directed mutagenesis, dual-luciferase assays and chromatin immunoprecipitation with anti-E2F5-IgG coupled with qPCR confirmed recruitment of E2F5 on TFPI2, MMP-2 and MMP-9 promoters. RNAi-mediated knockdown of E2F5 expression in PC3 caused a significant alteration of cell migration while that of TFFI2 resulted in a modest change. Abrogation of E2F5 and TFPI2 expression was associated with significant changes in the gelatinolytic activity of active forms of MMP-2 and MMP-9. Moreover, E2F5, MMP-2 and MMP-9 levels were elevated in biopsies of PCa patients relative to that of benign hyperplasia, while TFPI2 expression was reduced. MMP-9 was coimmunoprecipitated with anti-TFPI2-IgG in PCa tissue samples suggesting a direct interaction between the proteins. Finally, artemisinin treatment in PC3 cells repressed E2F5 along with MMP-2/MMP-9 while triggering TFPI2 expression which alleviated PC3 aggressiveness possibly through inhibition of MMP activities. Together, our study reinstates an oncogenic role of E2F5 which operates as a dual-function transcription factor for its targets TFPI2, MMP-2 and MMP-9 and promotes cellular invasiveness. This study also indicates a therapeutic potential of artemisinin, a natural compound which acts by correcting dysfunctional E2F5/TFPI2/MMP axis in PCa.


Assuntos
Biomarcadores Tumorais/metabolismo , Fator de Transcrição E2F5/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias da Próstata/patologia , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Fator de Transcrição E2F5/genética , Glicoproteínas/genética , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Invasividade Neoplásica , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas
12.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-31965980

RESUMO

Accumulating evidences indicate the involvement of epigenetic deregulations in cancer. While some epigenetic regulators with aberrant functions in cancer are targeted for improving therapeutic outcome in patients, reinstating the functions of tumor-suppressor-like epigenetic regulators might further potentiate anti-cancer therapies. Epigenetic reader zinc-finger MYND-type-containing 8 (ZMYND8) has been found to be endowed with multiple anti-cancer functions like inhibition of tumor cell migration and proliferation. Here, we report another novel tumor suppressor role of ZMYND8 as an inducer of differentiation in breast cancer cells, by upregulating differentiation genes. Interestingly, we also demonstrated that ZMYND8 mediates all its antitumor roles through a common dual-histone mark binding to H4K16Ac and H3K36Me2. We validated these findings by both biochemical and biophysical analyses. Furthermore, we also confirmed the differentiationinducing potential of ZMYND8 in vivo, using 4T1 murine breast cancer model in Balb/c mice. Differentiation therapy holds great promise in cancer therapy, since it is non-toxic and makes the cancer cells therapysensitive. In this scenario, we propose epigenetic reader ZMYND8 as a potential therapeutic candidate for differentiation therapy in breast cancer.


Assuntos
Neoplasias da Mama/genética , Epigênese Genética , Histonas/genética , Proteínas Supressoras de Tumor/genética , Animais , Neoplasias da Mama/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Camundongos , Ligação Proteica/genética , Ativação Transcricional/genética
13.
Biochemistry ; 59(4): 389-399, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31746185

RESUMO

Transcription factor 19 (TCF19) plays critical roles in type 1 diabetes and the maintenance of pancreatic ß cells. Recent studies have also implicated TCF19 in cell proliferation of hepatic carcinoma and non-small cell lung carcinoma; however, the mechanism underlying this regulation remains elusive. At the molecular level, TCF19 contains two modules, the plant homeodomain (PHD) finger and the forkhead-associated (FHA) domain, of unclear function. Here, we show that TCF19 mediates hepatocellular carcinoma HepG2 cell proliferation through its PHD finger that recognizes trimethylated lysine 4 of histone 3 (H3K4me3). W316 of the PHD finger of TCF19 is one of the critical residues eliciting this function. Whole genome microarray analysis and orthogonal cell-based assays identified a large subset of genes involved in cell survival and proliferation that depend on TCF19. Our data suggest that TCF19 acts as a pro-oncogene in hepatocellular carcinoma cells and that its functional PHD finger is critical in cell proliferation.


Assuntos
Histonas/metabolismo , Fatores de Transcrição/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Proteínas de Ligação a DNA/metabolismo , Células Hep G2 , Código das Histonas , Histonas/genética , Humanos , Neoplasias Hepáticas/metabolismo , Lisina/metabolismo , Metilação , Modelos Moleculares , Dedos de Zinco PHD/fisiologia , Ligação Proteica , Fatores de Transcrição/fisiologia
14.
Gen Comp Endocrinol ; 282: 113196, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163182

RESUMO

Seasonal activation of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis and gonadal development is initiated by gonadotropin-releasing hormone-I (GnRH) release from the hypothalamus. In photoperiodic species, the consistent annual change in photoperiod is the primary environmental signal affecting GnRH cell activity, including changes in the synthesis and secretion of this neuropeptide. Non-photoperiodic environmental cues such as energy availability also influence HPG axis activity, but the mechanisms mediating this influence, in particular on the GnRH system, are unclear. Understanding how the neuroendocrine system integrates environmental information is critical in determining the plasticity and adaptability of physiological responses to changing environments. The primary objective of this study was to investigate GnRH-mediated changes in HPG axis activity and gonadal development in response to energy availability in a wild bird. We hypothesized that negative energy balance inhibits HPG axis activity by affecting GnRH secretion. Moderate food restriction for several weeks in male house finches, Haemorhous mexicanus, decreased body condition and inhibited photoinduced testicular growth compared to birds fed ad libitum. Food restriction did not affect plasma luteinizing hormone (LH; a correlate of GnRH release) or plasma testosterone, but it enhanced the plasma LH response to an injection of the glutamatergic agonist, N-methyl-D-aspartate (NMDA). Thus, food restriction may decrease photoinduced HPG axis activation by acting centrally, in particular by attenuating the release of accumulated GnRH stores.


Assuntos
Tentilhões/metabolismo , Alimentos , Hormônio Liberador de Gonadotropina/metabolismo , Animais , Cloaca/fisiologia , Tentilhões/sangue , Hormônio Luteinizante/sangue , Masculino , Precursores de Proteínas , Testículo/metabolismo , Testosterona/sangue
15.
Nat Commun ; 10(1): 1398, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30923315

RESUMO

The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/ß-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.


Assuntos
Carcinogênese/genética , Código das Histonas/genética , Histonas/metabolismo , Dedos de Zinco PHD/genética , Neoplasias de Mama Triplo Negativas/genética , Ubiquitina-Proteína Ligases/genética , Animais , Caderinas/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , Transplante Heterólogo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/genética , Via de Sinalização Wnt
16.
EBioMedicine ; 37: 442-452, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30337251

RESUMO

BACKGROUND: Plasmodium falciparum and Plasmodium vivax are two major parasites responsible for malaria which remains a threat to almost 50% of world's population despite decade-long eradication program. One possible reason behind this conundrum is that the bases of clinical variability in malaria caused by either species are complex and poorly understood. METHODS: Whole-genome transcriptome was analyzed to identify the active and predominant pathways in the PBMC of P. falciparum and P. vivax infected malaria patients. Deregulated genes were identified and annotated using R Bioconductor and DAVID/KEGG respectively. Genetic and functional regulation of CD14, a prioritized candidate, were established by quantitative RT-PCR, genotyping using RFLP and resequencing, mapping of transcription factor binding using CONSITE and TFBIND, dual luciferase assay, western blot analysis, RNAi- mediated gene knockdown and chromatin-immunoprecipation. FINDINGS: The study highlighted that deregulation of host immune and inflammatory genes particularly CD14 as a key event in P. falciparum malaria. An abundance of allele-C of rs5744454, located in CD14 promoter, in severe malaria motivated us to establish an allele-specific regulation of CD14 by SP1. An enhancement of SP1 and CD14 expression was observed in artemisinin treated human monocyte cell line. INTERPRETATION: Our data not only reinstates that CD14 of TLR pathway plays a predominant role in P. falciparum malaria, it establishes a functional basis for genetic association of rs5744454 with P. falciparum severe malaria by demonstrating a cis-regulatory role of this promoter polymorphism. Moreover, the study points towards a novel pharmacogenetic aspect of artemisinin-based anti-malarial therapy. FUND: DST-SERB, Govt. of India, SR/SO/HS-0056/2013.


Assuntos
Regulação da Expressão Gênica , Leucócitos Mononucleares/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Malária Falciparum/metabolismo , Plasmodium falciparum , Plasmodium vivax , Fator de Transcrição Sp1/metabolismo , Transcriptoma , Adulto , Feminino , Humanos , Leucócitos Mononucleares/parasitologia , Leucócitos Mononucleares/patologia , Malária Vivax , Masculino , Pessoa de Meia-Idade
17.
Apoptosis ; 23(11-12): 679-694, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30196356

RESUMO

A novel activating peptide was designed and synthesized from V. cholerae hemagglutinine protease (HAP) mediated cleavage site of mouse PAR1. The peptide "PFISED" interacts with PAR1 in a new site which is different from its thrombin mediated conventional activation site and induced a series of new downstream signaling pathways. The peptide showed apoptosis in human and mouse breast (MCF-7 and EAC) and colon (HT29 and CT26) cancer cells where as in the same peptide concentration in normal human breast epithelial cells (MCF-10A), normal human fibroblast cells (MRC-5), normal mouse peritoneal macrophage cells and normal mouse breast and colon tissues did not show any effect. Treatment with this peptide enhanced the survival kinetics of EAC induced mice. The peptide mediated apoptosis was inhibited in presence of PAR1 inhibitor and was significantly reduced in si-PAR1 treated cells that indicate the activating peptide "PFISED" induced PAR1 mediated apoptosis of colon and breast cancer cells. This peptide induced over expression and activation of PAR1 and its downstream MAP kinase and NFκB signaling pathways. These signaling pathways enhanced the cellular ROS level to kill malignant cells. We report a novel pro-apoptotic peptide which can selectively kill malignant cells via its specific target receptor PAR1 which is over expressed in the malignant cells and can be used as a molecular target therapy for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Neoplasias do Colo/patologia , Peptídeos/farmacologia , Receptor PAR-1/metabolismo , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Inibidores de Caspase/farmacologia , Linhagem Celular , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Células MCF-7 , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Receptor PAR-1/antagonistas & inibidores , Receptor PAR-1/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Biol Chem ; 293(25): 9651, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934366
19.
J Biol Chem ; 293(20): 7905-7906, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29777018

RESUMO

Gluconeogenesis in the liver converts lipids and several other noncarbohydrate precursors into glucose, ensuring that blood sugar levels are maintained at healthy levels, especially during fasting. Effective regulation of gluconeogenesis is therefore critical for maintaining systemic metabolic homeostasis. Zhang and colleagues have discovered that the ubiquitous transcriptional regulator nuclear factor Y (NF-Y) confers cAMP responsiveness to key gluconeogenic genes and up-regulates hepatic glucose production. The study expands our understanding of transcriptional regulation of hepatic gluconeogenesis and also presents critical insights into the function of NF-Y in the liver.


Assuntos
Gluconeogênese , Fatores de Transcrição , Animais , Fator de Ligação a CCAAT , Plumas , Glucose , Hepatócitos , Fígado , Camundongos , Açúcares
20.
ACS Appl Mater Interfaces ; 10(5): 4582-4589, 2018 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-29338178

RESUMO

Herein we have engineered a smart nuclear targeting thiol-modified riboflavin-gold nano assembly, RfS@AuNPs, which accumulates selectively in the nucleus without any nuclear-targeting peptides (NLS/RGD) and shows photophysically in vitro DNA intercalation. A theoretical model using Molecular Dynamics has been developed to probe the mechanism of formation and stability as well as dynamics of the RfS@AuNPs in aqueous solution and within the DNA microenvironment. The RfS@AuNPs facilitate the binucleated cell formation that is reflected in the significant increase of DNA damage marker, γ-H2AX as well as the arrest of most of the HeLa cells at the pre-G1 phase indicating cell death. Moreover, a significant upregulation of apoptotic markers confirms that the cell death occurs through the apoptotic pathway. Analyses of the microarray gene expression of RfS@AuNPs treated HeLa cells show significant alterations in vital biological processes necessary for cell survival. Taken together, our study reports a unique nuclear targeting mechanism through targeting the riboflavin receptors, which are upregulated in cancer cells and induce apoptosis in the targeted cells.


Assuntos
Dano ao DNA , Apoptose , Linhagem Celular Tumoral , Ouro , Células HeLa , Humanos , Riboflavina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...