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1.
Cell Death Dis ; 15(1): 74, 2024 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-38242874

RESUMO

Copy number variations (CNVs) play a vital role in regulating genes expression and tumorigenesis. We explored the copy number alterations in early-stage lung adenocarcinoma using high-throughput sequencing and nucleic acid flight mass spectrometry technology, and found that 8q22.1-22.2 is frequently amplified in lung adenocarcinoma tissues. COX6C localizes on the region and its expression is notably enhanced that driven by amplification in lung adenocarcinoma. Knockdown of COX6C significantly inhibits the cell proliferation, and induces S-G2/M cell cycle arrest, mitosis deficiency and apoptosis. Moreover, COX6C depletion causes a deficiency in mitochondrial fusion, and impairment of oxidative phosphorylation. Mechanistically, COX6C-induced mitochondrial deficiency stimulates ROS accumulation and activates AMPK pathway, then leading to abnormality in spindle formation and chromosome segregation, activating spindle assemble checkpoint, causing mitotic arrest, and ultimately inducing cell apoptosis. Collectively, we suggested that copy amplification-mediated COX6C upregulation might serves as a prospective biomarker for prognosis and targeting therapy in patients with lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Proliferação de Células , Complexo IV da Cadeia de Transporte de Elétrons , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Variações do Número de Cópias de DNA/genética , Pontos de Checagem da Fase G2 do Ciclo Celular , Neoplasias Pulmonares/patologia , Mitose/genética , Espécies Reativas de Oxigênio/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo
2.
Commun Biol ; 7(1): 18, 2024 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-38177713

RESUMO

Mitochondrial transcription termination factor 3 (MTERF3) negatively regulates mitochondrial DNA transcription. However, its role in hepatocellular carcinoma (HCC) progression remains elusive. Here, we investigate the expression and function of MTERF3 in HCC. MTERF3 is overexpressed in HCC tumor tissues and higher expression of MTERF3 positively correlates with poor overall survival of HCC patients. Knockdown of MTERF3 induces mitochondrial dysfunction, S-G2/M cell cycle arrest and apoptosis, resulting in cell proliferation inhibition. In contrast, overexpression of MTERF3 promotes cell cycle progression and cell proliferation. Mechanistically, mitochondrial dysfunction induced by MTERF3 knockdown promotes ROS accumulation, activating p38 MAPK signaling pathway to suppress HCC cell proliferation. In conclusion, ROS accumulation induced by MTERF3 knockdown inhibits HCC cell proliferation via p38 MAPK signaling pathway suggesting a promising target in HCC patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Doenças Mitocondriais , Proteínas Mitocondriais , Fatores de Transcrição , Humanos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Hepáticas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , Proteínas Mitocondriais/genética
3.
Discov Oncol ; 14(1): 214, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-38008882

RESUMO

Small GTPases regulate multiple important cellular behaviors and their activities are strictly controlled by a mass of regulators. The dysfunction or abnormal expression of small GTPases or their regulators was frequently observed in various cancers. Here, we analyzed the expression and prognostic correlation of several GTPases and related regulators based on the TCGA database and found that Ankyrin Repeat and PH Domain 1 (ARAP1), a GTPase activating protein (GAP), is reduced in lung adenocarcinoma tissues compared to normal tissues and displays a positive correlation with overall survival (OS) and progression-free survival (PFS) of patients with lung adenocarcinoma. qPCR and western blot verified that ARAP1 is frequently downregulated in lung adenocarcinoma tumor tissues and cancer cells, and its downregulation might be mediated by epigenetic modification. Moreover, metastatic assays showed that overexpression of ARAP1 significantly inhibits metastasis of lung adenocarcinoma in vitro and in vivo. We further demonstrated that Rho signaling inhibition, mediated by RhoGAP activity of ARAP1, majorly contributes to suppressing migration and invasion of lung adenocarcinoma cancer cells via inhibiting stress fibers formation. In summary, this study indicates that ARAP1 may serve as a potential prognostic predictor and a metastatic suppressor in lung adenocarcinoma via its RhoGAP activity.

4.
iScience ; 26(8): 107469, 2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37588167

RESUMO

Long non-coding RNAs (lncRNAs) have been implicated in diverse biological processes. However, the functional mechanisms have not yet been fully explored. Characterizing the interactions of lncRNAs with chromatin is central to determining their functions but, due to precise and efficient approaches lacking, our understanding of their functional mechanisms has progressed slowly. In this study, we demonstrate that a nuclear lncRNA linc1393 maintains mouse ESC pluripotency by recruiting SET1A near its binding sites, to establish H3K4me3 status and activate the expression of specific pluripotency-related genes. Moreover, we characterized the principles of lncRNA-chromatin interaction and transcriptional regulation. Accordingly, we developed a computational framework based on the XGBoost model, LncTargeter, to predict the targets of a given lncRNA, and validated its reliability in various cellular contexts. Together, these findings elucidate the roles and mechanisms of lncRNA on pluripotency maintenance, and provide a promising tool for predicting the regulatory networks of lncRNAs.

5.
Cell Death Dis ; 14(2): 89, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36750557

RESUMO

Ribosome biogenesis (RiBi) plays a pivotal role in carcinogenesis by regulating protein translation and stress response. Here, we find that RRP15, a nucleolar protein critical for RiBi and checkpoint control, is frequently upregulated in primary CRCs and higher RRP15 expression positively correlated with TNM stage (P < 0.0001) and poor survival of CRC patients (P = 0.0011). Functionally, silencing RRP15 induces ribosome stress, cell cycle arrest, and apoptosis, resulting in suppression of cell proliferation and metastasis. Overexpression of RRP15 promotes cell proliferation and metastasis. Mechanistically, ribosome stress induced by RRP15 deficiency facilitates translation of TOP mRNA LZTS2 (Leucine zipper tumor suppressor 2), leading to the nuclear export and degradation of ß-catenin to suppress Wnt/ß-catenin signaling in CRC. In conclusion, ribosome stress induced by RRP15 deficiency inhibits CRC cell proliferation and metastasis via suppressing the Wnt/ß-catenin pathway, suggesting a potential new target in high-RiBi CRC patients.


Assuntos
Neoplasias Colorretais , beta Catenina , Humanos , Linhagem Celular Tumoral , beta Catenina/metabolismo , Neoplasias Colorretais/patologia , Proliferação de Células/genética , Ribossomos/metabolismo , Via de Sinalização Wnt/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Supressoras de Tumor/metabolismo
6.
J Mol Endocrinol ; 70(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36356262

RESUMO

The pathogenesis of nonalcoholic steatohepatitis (NASH), a severe stage of nonalcoholic fatty liver disease, is complex and implicates multiple cell interactions. However, therapies for NASH that target multiple cell interactions are still lacking. Melatonin (MEL) alleviates NASH with mechanisms not yet fully understood. Thus, we herein investigate the effects of MEL on key cell types involved in NASH, including hepatocytes, macrophages, and stellate cells. In a mouse NASH model with feeding of a methionine and choline-deficient (MCD) diet, MEL administration suppressed lipid accumulation and peroxidation, improved insulin sensitivity, and attenuated inflammation and fibrogenesis in the liver. Specifically, MEL reduced proinflammatory cytokine expression and inflammatory signal activation and attenuated CD11C+CD206- M1-like macrophage polarization in the liver of NASH mice. The reduction of proinflammatory response by MEL was also observed in the lipopolysaccharide-stimulated Raw264.7 cells. Additionally, MEL increased liver fatty acid ß-oxidation, leading to reduced lipid accumulation, and restored the oleate-loaded primary hepatocytes. Finally, MEL attenuated hepatic stellate cell (HSC) activation and fibrogenesis in the liver of MCD-fed mice and in LX-2 human HSCs. In conclusion, MEL acts on multiple cell types in the liver to mitigate NASH-associated phenotypes, supporting MEL or its analog as potential treatment for NASH.


Assuntos
Melatonina , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Melatonina/farmacologia , Melatonina/uso terapêutico , Melatonina/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Metionina/metabolismo , Metionina/farmacologia , Dieta , Modelos Animais de Doenças , Colina/metabolismo , Colina/farmacologia , Lipídeos
7.
Front Immunol ; 13: 1034992, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36524130

RESUMO

Background: Globally, lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths. It is a progressive disorder that arises from multiple genetic and environmental factors. Dysregulated expression of vesicle-mediated transport-related genes (VMTRGs) have been reported in several cancers. However, the prognostic significance of VMTRGs in LUAD has yet to be established. Methods: The VMTRG profiling data for 482 LUAD patients and 59 normal controls were downloaded from The Cancer Genome Altas (TCGA). Univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to construct and optimize the risk model. Several GEO datasets were used to validate the risk model. The roles of these genes were investigated via the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses. Differences in immune cell infiltrations between risk groups were evaluated using five algorithms. "pRRophetic" was used to investigate anti-cancer drug sensitivities in two groups. Expression of these five genes in LUAD samples and adjacent normal tissues were evaluated by qRT-PCR. Colony formation and wound healing assays were performed to assess the significance of CNIH1 and AP3S1 in LUAD cells. Results: We identified 85 prognosis-associated VMTRGs that could be constructed a risk model for LUAD patients, indicating their potential importance in LUAD development. The risk model including the five VMTRGs (CNIH1, KIF20A, GALNT2, GRIA1, and AP3S1) was associated with clinical outcomes. Tumor stage and risk score were found to be independent prognostic factors for LUAD patients. The five VMTRGs were also correlated with activation of the Notch and p53 signaling pathways. The risk model was significantly associated with immune responses and with high-level expression of immune checkpoints. High-risk group patients were more sensitive to several chemotherapeutic drugs and Lapatinib. Furthermore, CNIH1 and AP3S1 promoted LUAD cell growth and migration in vitro. Conclusion: We constructed a VMTRG-based risk model for effective prediction of prognostic outcomes for LUAD patients. The risk model was associated with immune infiltration levels. These five hub genes are potential targets for immune therapy combined with chemotherapy in LUAD.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Prognóstico , Adenocarcinoma de Pulmão/genética , Transporte Biológico , Adenocarcinoma/genética , Neoplasias Pulmonares/genética
8.
Acta Biochim Biophys Sin (Shanghai) ; 55(2): 304-313, 2022 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-36514224

RESUMO

Neoadjuvant therapy (NAT) for advanced colorectal cancer (ACRC) is a kind of well-evidenced therapy, yet a portion of ACRC patients have poor therapeutic response. To date, no suitable biomarker used for assessing NAT efficacy has been reported. Here, we collect 72 colonoscopy biopsy tissue specimens from ACRC patients before undergoing NAT and investigate the relationship between HOXA13 expression and NAT efficacy. The results show that HOXA13 expression in pretreated tumor specimens is negatively associated with tumor regression ( P<0.001) and progression-free survival ( P<0.05) in ACRC patients who underwent NAT. Silencing of HOXA13 or its regulator HOTTIP significantly enhances the chemosensitivity of colorectal cancer (CRC) cells, leading to an increase in cell apoptosis and the DNA damage response (DDR) to chemotherapeutic drug treatment. In contrast, HOXA13 overexpression causes a significant increase in chemoresistance in CRC cells. In summary, we find that the HOTTIP/HOXA13 axis is involved in regulating chemotherapeutic sensitivity in CRC cells by modulating the DDR and that HOXA13 serves as a promising marker for NAT efficacy prediction in ACRC patients.


Assuntos
Neoplasias Colorretais , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Regulação Neoplásica da Expressão Gênica , Terapia Neoadjuvante , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Biomarcadores
9.
J Appl Stat ; 49(14): 3677-3692, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36246863

RESUMO

Variable selection is fundamental to high dimensional statistical modeling, and many approaches have been proposed. However, existing variable selection methods do not perform well in presence of outliers in response variable or/and covariates. In order to ensure a high probability of correct selection and efficient parameter estimation, we investigate a robust variable selection method based on a modified Huber's function with an exponential squared loss tail. We also prove that the proposed method has oracle properties. Furthermore, we carry out simulation studies to evaluate the performance of the proposed method for both pn. Our simulation results indicate that the proposed method is efficient and robust against outliers and heavy-tailed distributions. Finally, a real dataset from an air pollution mortality study is used to illustrate the proposed method.

10.
Cell Discov ; 8(1): 96, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36167681

RESUMO

Metabolism feeds into the regulation of epigenetics via metabolic enzymes and metabolites. However, metabolic features, and their impact on epigenetic remodeling during mammalian pre-implantation development, remain poorly understood. In this study, we established the metabolic landscape of mouse pre-implantation embryos from zygote to blastocyst, and quantified some absolute carbohydrate metabolites. We integrated these data with transcriptomic and proteomic data, and discovered the metabolic characteristics of the development process, including the activation of methionine cycle from 8-cell embryo to blastocyst, high glutaminolysis metabolism at blastocyst stage, enhanced TCA cycle activity from the 8-cell embryo stage, and active glycolysis in the blastocyst. We further demonstrated that oxidized nicotinamide adenine dinucleotide (NAD+) synthesis is indispensable for mouse pre-implantation development. Mechanistically, in part, NAD+ is required for the exit of minor zygotic gene activation (ZGA) by cooperating with SIRT1 to remove zygotic H3K27ac. In human, NAD+ supplement can promote the removal of zygotic H3K27ac and benefit pre-implantation development. Our findings demonstrate that precise and timely regulation of minor ZGA is controlled by metabolic dynamics, and enhance our understanding of the metabolism of mammalian early embryos.

11.
Acta Biochim Biophys Sin (Shanghai) ; 54(7): 940-951, 2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35882623

RESUMO

More and more patients with advanced colorectal cancer (CRC) have benefited from surgical resection or ablation following neoadjuvant chemoradiotherapy (nCRT), but nCRT may be ineffective and have potential risks to some patients. Therefore, it is necessary to discover effective biomarkers for predicting the nCRT efficacy in CRC patients. Chromokinesin Kif4A plays a critical role in mitosis, DNA damage repair and tumorigenesis, but its relationship with nCRT efficacy in advanced CRC remains unclear. Here, we find that Kif4A expression in pretreated tumor tissue is positively correlated with poorer tumor regression after receiving nCRT ( P=0.005). Knockdown of endogenous Kif4A causes an increased sensitivity of CRC cells to chemotherapeutic drugs 5-fluorouracil (5-FU) and Cisplatin (DDP), while overexpression of Kif4A enhances resistance of CRC cells to the chemotherapeutic drugs. Furthermore, depending on its motor domain and tail domain, Kif4A regulates DNA damage response (DDR) induced by 5-FU or DDP treatment in CRC cells. In conclusion, we demonstrate that Kif4A may be a potential independent biomarker for predicting the nCRT efficacy in advanced CRC patients, and Kif4A regulates chemosensitivity of CRC cells through controlling DDR.


Assuntos
Neoplasias Colorretais , Terapia Neoadjuvante , Cisplatino/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Dano ao DNA , Fluoruracila/farmacologia , Humanos , Cinesinas/genética
12.
Int J Med Sci ; 16(8): 1132-1141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523176

RESUMO

Ribosomal biogenesis is responsible for protein synthesis in all eukaryotic cells. Perturbation of ribosomal biogenesis processes can cause dysfunctions of protein synthesis and varieties of human diseases. In this study, we examine the role of RPL15, a large ribosomal subunit protein, in human colon carcinogenesis. Our results reveal that RPL15 is remarkably upregulated in human primary colon cancer tissues and cultured cell lines when compared with paired non-cancerous tissues and non-transformed epithelium cells. Elevated expression of RPL15 in colon cancer tissues is closely correlated with clinicopathological characteristics in patients. We determine the effects of RPL15 on nucleolar maintenance, ribosomal biogenesis and cell proliferation in human cells. We show that RPL15 is required for maintenance of nucleolar structure and formation of pre-60S subunits in the nucleoli. Depletion of RPL15 causes ribosomal stress, resulting in a G1-G1/S cell cycle arrest in non-transformed human epithelium cells, but apoptosis in colon cancer cells. Together, these results indicate that RPL15 is involved in human colon carcinogenesis and might be a potential clinical biomarker and/or target for colon cancer therapy.


Assuntos
Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Proteínas Ribossômicas/metabolismo , Idoso , Apoptose/genética , Pontos de Checagem do Ciclo Celular , Nucléolo Celular/metabolismo , Nucléolo Celular/ultraestrutura , Neoplasias do Colo/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HeLa , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Ribossômicas/genética
13.
J Mol Cell Biol ; 10(4): 358-370, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29771379

RESUMO

The chromokinesin Kif4A controls proper chromosome condensation, congression/alignment, and cytokinesis to ensure faithful genetic inheritance. Here, we report that Cdk phosphorylation of human Kif4A at T1161 licenses Kif4A chromosomal localization, which, in turn, controls Kif4A early mitotic function. Phosphorylated Kif4A (Kif4AWT) or Cdk phospho-mimetic Kif4A mutant (Kif4ATE) associated with chromosomes and condensin I (non-SMC subunit CAP-G and core subunit SMC2) to regulate chromosome condensation, spindle morphology, and chromosome congression/alignment in early mitosis. In contrast, Cdk non-phosphorylatable Kif4A mutant (Kif4ATA) could neither localize on chromosomes nor associate with CAP-G and SMC2. Furthermore, Kif4ATA could not rescue defective chromosome condensation, spindle morphology, or chromosome congression/alignment in cells depleted of endogenous Kif4A, which activated a mitotic checkpoint and delayed early mitotic progression. However, targeting Kif4ATA to chromosomes by fusion of Kif4ATA with Histone H1 resulted in restoration of chromosome and spindle functions of Kif4A, similar to Kif4AWT and Kif4ATE, in cells depleted of endogenous Kif4A. Thus, our results demonstrate that Cdk phosphorylation-licensed chromosomal localization of Kif4A plays a critical role in regulating early mitotic functions of Kif4A that are important for early mitotic progression.


Assuntos
Quinases Ciclina-Dependentes/metabolismo , Cinesinas/metabolismo , Mitose , Adenosina Trifosfatases/análise , Adenosina Trifosfatases/metabolismo , Sequência de Aminoácidos , Animais , Cromossomos Humanos/metabolismo , Cromossomos Humanos/ultraestrutura , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Humanos , Cinesinas/análise , Modelos Moleculares , Complexos Multiproteicos/análise , Complexos Multiproteicos/metabolismo , Fosforilação , Fuso Acromático/metabolismo , Fuso Acromático/ultraestrutura
14.
Oncotarget ; 9(1): 512-523, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29416632

RESUMO

HDAC inhibitors (HDACis) have been demonstrated with profound antiproliferative activities in various tumor types. Previously, we screened several polyoxometalate HDACis based on our p21 luciferase promoter system and demonstrated that such HDACis have antitumor activity. Here, we further investigate the antitumor mechanism of PAC-320, a compound among the polyoxometalates, in human prostate cancer. We demonstrate that PAC-320 is a broad-spectrum HDACi and could inhibit growth of prostate cancer cells in vitro and in vivo. Furthermore, we find that PAC-320 induces cell cycle arrest at G2/M phase and apoptosis. Mechanically, PAC-320 induced cell cycle arrest is associated with an increase of p21 and decrease of cyclin A and cyclin B1, while PAC-320 induced apoptosis is mediated through mitochondria apoptotic pathway and is closely associated with increase of BH3-only proteins Noxa and Hrk. Meanwhile, we demonstrate that p38 MAPK pathway is involved in PAC-320 induced antiproliferative activities in prostate cancer. Taken together, our data indicates that PAC-320 has potent prostate cancer inhibitory activity in vitro and in vivo, which is mediated by G2/M cell cycle arrest and apoptosis.

15.
J Zhejiang Univ Sci B ; 18(12): 1046-1054, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29204984

RESUMO

Multidrug resistance (MDR) is the major impediment to cancer chemotherapy. The expression of lung resistance-related protein (LRP), a non-ATP-binding cassette (ABC) transporter, is high in tumor cells, resulting in their resistance to a variety of cytotoxic drugs. However, the function of LRP in tumor drug resistance is not yet explicit. Our previous studies had shown that Kinesin KIF4A was overexpressed in cisplatin (DDP)-resistant human lung adenocarcinoma cells (A549/DDP cells) compared with A549 cells. The expression of KIF4A in A549 or A549/DDP cells significantly affects cisplatin resistance but the detailed mechanisms remain unclear. Here, we performed co-immunoprecipitation experiments to show that the tail domain of KIF4A interacted with the N-terminal of LRP. Immunofluorescence images showed that both the ability of binding to LRP and the motility of KIF4A were essential for the dispersed cytoplasm distribution of LRP. Altogether, our results shed light on a potential mechanism in that motor protein KIF4A promotes drug resistance of lung adenocarcinoma cells through transporting LRP-based vaults along microtubules towards the cell membrane. Thus KIF4A might be a cisplatin resistance-associated protein and serves as a potential target for chemotherapeutic drug resistance in lung cancer.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Cinesinas/metabolismo , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismo , Células A549 , Cisplatino/farmacologia , Citoplasma/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Microscopia de Fluorescência , Microtúbulos/metabolismo , Domínios Proteicos , Transporte Proteico , RNA Interferente Pequeno/metabolismo
16.
Oncotarget ; 8(8): 13240-13252, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28099941

RESUMO

The nucleolus controls ribosome biogenesis and its perturbation induces nucleolar stress that inhibits cell cycle progression and activates checkpoint responses. Here, we investigate the roles of ribosomal RNA processing protein, RRP15, in nucleolar formation, ribosome biogenesis, cell cycle progression and checkpoint control in human cells. RRP15 is localized in the nucleolus and required for nucleolar formation. In contrast to the budding yeast Rrp15p that was reported as a component of pre-60S subunits, RRP15 is found in both pre-40S and pre-60S subunits and involved in regulating rRNA transcription and ribosome biogenesis. Perturbation of RRP15 induces nucleolar stress that activates RPL5/RPL11/5S rRNA (RP)-Mdm2-p53 axis checkpoint response and arrests cells at G1-G1/S in p53-proficient non-transformed RPE1 cells but not in p53-deficient HeLa and MCF7 tumor cells. Instead, p53-deficient HeLa and MCF7 cells with RRP15-dependent nucleolar stress enter S-phase with S-phase perturbation that activates ATR-Chk1- γH2AX axis DNA replication/damage checkpoint response, delaying S-G2/M progression and, ultimately, causing cell death. The selective checkpoint response, cell cycle inhibition and/or cytotoxicity induced by RRP15-dependent nucleolar stress in p53-proficient non-transformed cells and p53-deficient tumor cells suggest that RRP15 might be a potential target for cancer therapy.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Nucléolo Celular/genética , Proteínas Ribossômicas/genética , Ribossomos/genética , Linhagem Celular Transformada , Nucléolo Celular/metabolismo , Proliferação de Células/genética , Células HeLa , Humanos , Immunoblotting , Células MCF-7 , Microscopia de Fluorescência , Interferência de RNA , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , Fase S/genética , Transdução de Sinais/genética , Imagem com Lapso de Tempo/métodos , Transcrição Gênica , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
PLoS One ; 7(7): e40943, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22808286

RESUMO

All-trans retinoic acid (ATRA) has been widely investigated for treatments of many cancers including prostate cancer. HOXB13, silenced in androgen receptor-negative (AR(-)) prostate cancer cells, plays a role in AR(-) prostate cancer cell growth arrest. In this study we intended to elucidate the mechanisms that are involved in the proliferation inhibition of AR(-) prostate cancer cells triggered by ATRA. We discovered that ATRA was able to induce the growth arrest and to increase HOXB13 expression in AR(-) prostate cancer cells. Both EZH2 and DNMT3b participated in the repression of HOXB13 expression through an epigenetic mechanism involving DNA and histone methylation modifications. Specifically, EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. Moreover, ATRA could upregulate HOXB13 through decreasing EZH2 and DNMT3b expressions and reducing their interactions with the HOXB13 promoter. Concurrently, the methylation level of the HOXB13 promoter was reduced upon the treatment of ATRA. Results from this study implicated a novel effect of ATRA in inhibition of the growth of AR(-) resistant human prostate cancer cells through alteration of HOXB13 expression as a result of epigenetic modifications.


Assuntos
Metilação de DNA/genética , Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Tretinoína/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste , Repressão Epigenética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Modelos Genéticos , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/enzimologia , Ligação Proteica/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , DNA Metiltransferase 3B
19.
Breast Cancer Res Treat ; 131(1): 65-73, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21465172

RESUMO

Polycomb group (PcG) proteins have recently been shown related to cancer development. The PcG protein EZH2 is involved in progression of prostate and breast cancers, and has been identified as a molecular marker in breast cancer. Nevertheless, the molecular mechanism by which PcG proteins regulate cancer progression and malignant metastasis is still unclear. PcG proteins methylate H3K27 in undifferentiated epithelial cells, resulting in the repression of differentiation genes such as HOX. FOXC1 is a member of the Forkhead box transcription factor family, which plays an important role in differentiation, and is involved in eye development. We discovered in this study that the expression of FOXC1 gene was negatively correlated to that of PcG genes, i.e., Bmi1, EZH2, and SUZ12, in MCF-7 and MDA-MB-231 cells. To investigate the regulatory effects of PcG proteins on FOXC1 gene, the two cell lines were transfected with either expression plasmids or siRNA plasmids of Bmi1, EZH2, and SUZ12, and we found that PcGs, especially EZH2, could repress the transcription of FOXC1 gene. Chromatin immunoprecipitation (ChIP) assay showed that histone methylation and acetylation modifications played critical roles in this regulatory process. When FOXC1 was stably transfected into MDA-MB-231 cells, the migration and invasion of the cells were repressed. Moreover, the tumorigenicity and the spontaneous metastatic capability regulated by FOXC1 were determined by using an orthotropic xenograft tumor model of athymic mice with the FOXC1-MDA-MB-231HM and the GFP-MDA-MB-231HM cells, and the results showed that FOXC1 in MDA-MB-231HM cells inhibited migration and invasion in vitro and reduced the pulmonary metastasis in vivo. Data presented in this report contribute to the understanding of the mechanisms by which EZH2 participates in tumor development.


Assuntos
Neoplasias da Mama/patologia , Fatores de Transcrição Forkhead/metabolismo , Proteínas Repressoras/metabolismo , Acetilação , Animais , Neoplasias da Mama/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Proteínas de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Complexo Repressor Polycomb 1 , Complexo Repressor Polycomb 2 , Proteínas do Grupo Polycomb , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção/métodos
20.
PLoS One ; 6(7): e22666, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21829474

RESUMO

Epithelial to mesenchymal transition (EMT) plays an important role in many biological processes. The latest studies revealed that aggressive breast cancer, especially the triple-negative breast cancer (TNBC) subtype was frequently associated with apparent EMT, but the mechanisms are still unclear. NEDD9/HEF1/Cas-L is a member of the Cas protein family and was identified as a metastasis marker in multiple cancer types. In this study, we wished to discern the role of NEDD9 in breast cancer progression and to investigate the molecular mechanism by which NEDD9 regulates EMT and promotes invasion in triple-negative breast cancer. We showed that expression of NEDD9 was frequently upregulated in TNBC cell lines, and in aggressive breast tumors, especially in TNBC subtype. Knockdown of endogenous NEDD9 reduced the migration, invasion and proliferation of TNBC cells. Moreover, ectopic overexpression of NEDD9 in mammary epithelial cells led to a string of events including the trigger of EMT, activation of ERK signaling, increase of several EMT-inducing transcription factors and promotion of their interactions with the E-cadherin promoter. Data presented in this report contribute to the understanding of the mechanisms by which NEDD9 promotes EMT, and provide useful clues to the evaluation of the potential of NEDD9 as a responsive molecular target for TNBC chemotherapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Western Blotting , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Movimento Celular , Proliferação de Células , Imunoprecipitação da Cromatina , Ensaio de Unidades Formadoras de Colônias , Feminino , Humanos , Luciferases/metabolismo , Sistema de Sinalização das MAP Quinases , Invasividade Neoplásica , Fosfoproteínas/genética , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas , Cicatrização
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