p53-Dependent and Cell Specific Epigenetic Regulation of the Polo-like kinases under Oxidative Stress
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{"title"=>"p53-dependent and cell specific epigenetic regulation of the polo-like kinases under oxidative stress", "type"=>"journal", "authors"=>[{"first_name"=>"Alejandra", "last_name"=>"Ward", "scopus_author_id"=>"33068444900"}, {"first_name"=>"John W.", "last_name"=>"Hudson", "scopus_author_id"=>"36888424400"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"373071460", "pmid"=>"24498222", "isbn"=>"2984762010", "doi"=>"10.1371/journal.pone.0087918", "sgr"=>"84899562295", "scopus"=>"2-s2.0-84899562295"}, "id"=>"9752c214-3f74-3b99-9c8e-488f2b10ea33", "abstract"=>"The polo-like kinase {(PLKs)} family, consisting of five known members, are key regulators of important cell cycle processes, which include mitotic entry, centrosome duplication, spindle assembly, and cytokinesis. The {PLKs} have been implicated in a variety of cancers, such as hepatocellular carcinoma {(HCC),} with {PLK1} typically overexpressed and {PLKs} 2-5 often downregulated. Altered expression of the {PLKs} in malignancy is often correlated with aberrant promoter methylation. Epigenetic marks are dynamic and can be modified in response to external environmental stimuli. The aim of our study was to determine if oxidative stress, a common feature of solid tumours, would induce changes to the promoter methylation of the {PLKs} resulting in changes in expression. We examined the promoter methylation status via {MSP} and subsequent expression levels of the {PLK} family members under exposure to hypoxic conditions or reactive oxygen species {(ROS).} Interestingly, murine embryonic fibroblasts exposed to hypoxia and {ROS} displayed significant hypermethylation of Plk1 and Plk4 promoter regions post treatment. Corresponding proteins were also depleted by 40% after treatment. We also examined the {HCC-derived} cell lines {HepG2} and {Hep3B} and found that for {PLK1} and {PLK4,} the increase in hypermethylation was correlated with the presence of functional p53. In p53 wild-type cells, {HepG2,} both {PLK1} and {PLK4} were repressed with treatment, while in the p53 null cell line, {Hep3B,} {PLK4} protein was elevated in the presence of hypoxia and {ROS.} This was also the case for {ROS-treated,} p53 null, osteosarcoma cells, Saos-2, where the {PLK4} promoter became hypomethylated and protein levels were elevated. Our data supports a model in which the {PLKs} are susceptible to epigenetic changes induced by microenvironmental cues and these modifications may be p53-dependent. This has important implications in {HCC} and other cancers, where epigenetic alterations of the {PLKs} could contribute to tumourigenesis and disease progression.", "link"=>"http://www.mendeley.com/research/p53dependent-cell-specific-epigenetic-regulation-pololike-kinases-under-oxidative-stress", "reader_count"=>26, "reader_count_by_academic_status"=>{"Researcher"=>6, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>1, "Student > Master"=>5, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>6, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>1, "Student > Master"=>5, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>5, "Physics and Astronomy"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Spain"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1370853"], "description"=>"<p>(a) <i>PLK</i> promoter methylation was determined by methylation-specific PCR; U = unmethylated, M = methylated. Fully methylated HeLa DNA was used as a positive control (+M), no template was added to the negative control (−M). (b) Fold change in plk1 transcripts. All qPCR values have been normalized to the respective untreated samples. Here the mean value of three independent experiments are depicted with error bars representing the +/− SD. (c) PLK1 and PLK2 protein levels in U2-OS and SAOS-2 cells treated with hypoxia and ROS. GAPDH was used as a loading control. (−) indicates lysates extracted from untreated samples, (+) represents lysates extracted from cells exposed to either hypoxia or ROS. (d,e) PLK2 and PLK3 transcripts as determined by qPCR. ND = not detectable. (g) Transcript changes for PLK4 in cells exposed to ROS and hypoxia. (h) PLK4 protein levels in sarcoma cells treated with hypoxia and ROS (+) compared to the untreated counterpart (−). GAPDH was used as a loading control. (i) PLK4 protein levels quantified with densitometry analysis of the Western blot images. The histogram is representative of the mean from three independent experiments with error bars showing the +/− SD. * denotes significance with a p<0.05.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "genetics", "epigenetics", "DNA modification", "gene expression", "Model organisms", "Animal models", "mouse", "oncology", "Basic cancer research", "Tumor physiology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "promoter", "methylation", "sarcoma-derived", "cells", "grown", "oxidative"], "article_id"=>921792, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Alejandra Ward", "John W. Hudson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087918.g005", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Examination_of_PLK_promoter_methylation_in_sarcoma_derived_cells_grown_in_the_presence_of_oxidative_stress_/921792", "title"=>"Examination of <i>PLK</i> promoter methylation in sarcoma-derived cells grown in the presence of oxidative stress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 02:47:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1370851"], "description"=>"<p>(a) Promoter methylation status of the plks examined in HCC-derived cells HepG2 and Hep3B; U = unmethylated, M = methylated. Fully methylated HeLa DNA was used as a positive control (+M), no template was added to the negative control (−M). (b) Post hypoxia, PLK4 transcripts were assessed <i>via</i> qPCR in RNA extracted from HCC cells. All qPCR data is representative of the mean value of three independent experiments and error bars represent +/− SD. (c) PLK protein levels were examined post treatment from whole cell lysates. Actin was used as a loading control. (−) represents lysates from untreated cells, (+) lysates from cells grown in the presence of hypoxia. (d) Quantification of protein levels using densitometry. Levels have been normalized to the respective untreated controls. Data is representative of the mean value of three independent experiments and error bars represent +/− SD. (e) The fold change of PLK1 transcripts as determined by qPCR. Values normalized to the respective untreated sample. (f) PLK2 and PLK3 analyzed and fold changed determine by normalization to the respective untreated samples. (g) Hif1α transcripts post hypoxia were determine by real-time PCR using a Taqman probe.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "genetics", "epigenetics", "DNA modification", "gene expression", "Model organisms", "Animal models", "mouse", "oncology", "Basic cancer research", "Tumor physiology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "modification", "promoter", "methylation", "hcc"], "article_id"=>921790, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Alejandra Ward", "John W. Hudson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087918.g003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hypoxia_induced_modification_of_PLK_promoter_methylation_in_HCC_cells_/921790", "title"=>"Hypoxia-induced modification of <i>PLK</i> promoter methylation in HCC cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 02:47:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1370861"], "description"=>"<p>Previous data has established that p53 can regulate both PLK1 and PLK4 expression through protein-protein interactions. Here we have incorporated our observations into the known mechanisms of the p53-PLK regulatory axis (a.) Our data suggests that when oxidative stress upregulates p53 activity, this can lead to downstream effects that can potentially induce the epigenetic silencing of the <i>PLKs</i>. In wild type p53 cells, these mechanisms can include the recruitment and/or collaboration with epigenetic modifiers such as DNMT1, DNMT3a or histone deacetylases (HDACs). (b) However, oxidative stress in the absence of p53, these vital inhibitory interactions carried out through the p53 pathway are abolished. PLK1 and PLK4 expression thus carries on unhindered, potentially pushing the cell through the G2/M transition point with unrepaired DNA damage, resulting in genomic instability and aneuploidy, both of which are hallmarks of cancer.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "genetics", "epigenetics", "DNA modification", "gene expression", "Model organisms", "Animal models", "mouse", "oncology", "Basic cancer research", "Tumor physiology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "p53", "oxidative"], "article_id"=>921800, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Alejandra Ward", "John W. Hudson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087918.g007", "stats"=>{"downloads"=>3, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_potential_role_for_p53_in_the_silencing_of_the_PLKs_as_a_result_of_oxidative_stress_/921800", "title"=>"A potential role for p53 in the silencing of the <i>PLKs</i> as a result of oxidative stress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 02:47:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1370864", "https://ndownloader.figshare.com/files/1370865"], "description"=>"<div><p>The polo-like kinase (PLKs) family, consisting of five known members, are key regulators of important cell cycle processes, which include mitotic entry, centrosome duplication, spindle assembly, and cytokinesis. The <i>PLKs</i> have been implicated in a variety of cancers, such as hepatocellular carcinoma (HCC), with PLK1 typically overexpressed and PLKs 2–5 often downregulated. Altered expression of the PLKs in malignancy is often correlated with aberrant promoter methylation. Epigenetic marks are dynamic and can be modified in response to external environmental stimuli. The aim of our study was to determine if oxidative stress, a common feature of solid tumours, would induce changes to the promoter methylation of the <i>PLKs</i> resulting in changes in expression. We examined the promoter methylation status <i>via</i> MSP and subsequent expression levels of the <i>PLK</i> family members under exposure to hypoxic conditions or reactive oxygen species (ROS). Interestingly, murine embryonic fibroblasts exposed to hypoxia and ROS displayed significant hypermethylation of <i>Plk1</i> and <i>Plk4</i> promoter regions post treatment. Corresponding proteins were also depleted by 40% after treatment. We also examined the HCC-derived cell lines HepG2 and Hep3B and found that for <i>PLK1</i> and <i>PLK4</i>, the increase in hypermethylation was correlated with the presence of functional p53. In p53 wild-type cells, HepG2, both <i>PLK1</i> and <i>PLK4</i> were repressed with treatment, while in the p53 null cell line, Hep3B, PLK4 protein was elevated in the presence of hypoxia and ROS. This was also the case for ROS-treated, p53 null, osteosarcoma cells, Saos-2, where the <i>PLK4</i> promoter became hypomethylated and protein levels were elevated. Our data supports a model in which the <i>PLKs</i> are susceptible to epigenetic changes induced by microenvironmental cues and these modifications may be p53-dependent. This has important implications in HCC and other cancers, where epigenetic alterations of the <i>PLKs</i> could contribute to tumourigenesis and disease progression.</p></div>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "genetics", "epigenetics", "DNA modification", "gene expression", "Model organisms", "Animal models", "mouse", "oncology", "Basic cancer research", "Tumor physiology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "p53-dependent", "epigenetic", "oxidative"], "article_id"=>921803, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Alejandra Ward", "John W. Hudson"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0087918.s001", "https://dx.doi.org/10.1371/journal.pone.0087918.s002"], "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/p53_Dependent_and_Cell_Specific_Epigenetic_Regulation_of_the_Polo_like_kinases_under_Oxidative_Stress/921803", "title"=>"p53-Dependent and Cell Specific Epigenetic Regulation of the <i>Polo-like kinases</i> under Oxidative Stress", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-01-31 02:47:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1370849"], "description"=>"<p>(a) MSP analysis shows the promoter methylation of <i>plk1</i> and <i>plk4</i> pre- and post-ROS treatment; U = unmethylated, M = methylated. Fully methylated NIH 3T3 DNA was used as a positive control (+M), no template was added to the negative control (−M). (b) Plk4 transcript levels determined by qPCR. All transcripts were normalized to the wild type untreated control. All qPCR data is representative of the mean value of three independent experiments and error bars represent +/− SD. (c) Plk1 and plk4 protein levels examined <i>via</i> Western blot analysis, actin was used as a loading control. (−) represents the lysates from untreated cells, (+) lysates from cells grown in the presence of ROS (d) Plk4 protein expression levels determined by densitometry. All densitometry data is representative of three independent experiments and the error bars represent +/− SD. * denotes significance with a p<0.05. (e) Plk1 transcripts of cells treated with ROS, the transcripts were normalized to the respective untreated samples. (f) The relative plk1 protein levels post treatment was normalized to the wild-type untreated samples. Levels determined by densitometric analysis of Western blot images. (g) An ELISA-based p53 activity assay. Relative activity was determined by normalizing values to the untreated samples. This data represents the mean value obtained over three independent experiments and error bars denote the +/− SD. (h) p53 protein levels in MEFs post treatment as determined by Western blot analysis. (i) Densitometry was performed on three independent experiments and all data has been normalized to the respective untreated. The mean expression is presented with error bars denoting +/− SD. * denotes significance with a p<0.05.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "genetics", "epigenetics", "DNA modification", "gene expression", "Model organisms", "Animal models", "mouse", "oncology", "Basic cancer research", "Tumor physiology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "epigenetic", "marks", "ros"], "article_id"=>921788, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Alejandra Ward", "John W. Hudson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087918.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Modification_of_plk1_and_plk4_epigenetic_marks_with_ROS_exposure_in_MEFs_/921788", "title"=>"Modification of <i>plk1</i> and <i>plk4</i> epigenetic marks with ROS exposure in MEFs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 02:47:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1370845"], "description"=>"<p>(a) DNA extracted from mouse embryonic fibroblasts grown under hypoxic conditions was bisulfite treated and then assessed for promoter methylation of <i>Plk1</i> and <i>Plk4</i> using methylation specific PCR; U = unmethylated, M = methylated. Fully methylated NIH 3T3 DNA was used as a positive control (+M), no template was added to the negative control (−M). (b) Plk4 transcripts were assessed using qPCR. Transcript levels were normalized to the wild type untreated sample. All qPCR data is representative of the mean value of three independent experiments and error bars represent +/− SD. (c) Western blot analysis to examine protein levels of Plk1 and Plk4 post hypoxic treatment. (−) represents the lysates from untreated cells, (+) lysates from cells were grown in the presence of hypoxia. (d) Densitometric analysis normalized to the levels of the wild-type untreated cells. Error bars represent +/− SD from three independent experiments. (e) The fold change of plk1 transcripts normalized to the respective untreated transcripts. (f) The percent of Plk1 protein expression relative to the untreated wild-type cells. * denotes significance with p<0.05. (g) RNA extracted from MEFs along with real-time PCR was used to determine Hif1α transcripts post hypoxia treatment.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "genetics", "epigenetics", "DNA modification", "gene expression", "Model organisms", "Animal models", "mouse", "oncology", "Basic cancer research", "Tumor physiology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "methylation", "promoter", "regions", "mefs", "hypoxic"], "article_id"=>921784, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Alejandra Ward", "John W. Hudson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087918.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Aberrant_methylation_of_plk1_and_plk4_promoter_regions_in_MEFs_under_hypoxic_stress_/921784", "title"=>"Aberrant methylation of <i>plk1</i> and <i>plk4</i> promoter regions in MEFs under hypoxic stress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 02:47:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1370857"], "description"=>"<p>An ELISA-based global methylation assay was performed to determine changes in global methylation levels due to oxidative stress as a result of hypoxia and ROS exposure. The histograms are representative of three independent experiments and the error bars depict the +/− SD. (a) In MEFs the values have been normalized to the untreated wild-type cells. (b,c) The values have been normalized to the respective untreated samples. (d) Western blot analysis was used to determine the levels of the DNMTs from whole cell lysates extracted from untreated (−) and treated (+) MEF cells.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "genetics", "epigenetics", "DNA modification", "gene expression", "Model organisms", "Animal models", "mouse", "oncology", "Basic cancer research", "Tumor physiology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "methylation", "hcc", "osteosarcoma", "cells", "dnmts"], "article_id"=>921796, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Alejandra Ward", "John W. Hudson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087918.g006", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_global_methylation_in_MEFs_HCC_and_osteosarcoma_cells_and_DNMTs_levels_in_MEFs_/921796", "title"=>"Analysis of global methylation in MEFs, HCC and osteosarcoma cells and DNMTs levels in MEFs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 02:47:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1370852"], "description"=>"<p>(a) A p53 activity assay was performed to confirm activation of p53 with genotoxic stress caused by ROS. The percent activity is the average of three independent experiments with error bars representing the +/− SD. (b) MSP analysis of <i>plk</i> promoter methylation; U = unmethylated, M = methylated. Fully methylated HeLa DNA was used as a positive control (+M), no template was added to the negative control (−M). (c) Plk1 transcript levels were examined and normalized to the respective untreated samples. All qPCR data is representative of the mean value of three independent experiments and are normalized to the untreated samples. Error bars represent +/− SD. (d) Western blot analysis of PLK protein levels. Actin was used as a loading control. (−) represents the lysates from untreated cells, (+) lysates from cells were grown in the presence of ROS. (e) The fold change in plk4 transcripts from cells exposed to ROS. (f) Quantification of PLK4 protein levels. Data is representative of three independent experiments and the error bars represent +/− SD. * denotes significance with a p<0.05. (g,h) PLK2 and PLK3 change in transcripts as determined by real time PCR.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "genetics", "epigenetics", "DNA modification", "gene expression", "Model organisms", "Animal models", "mouse", "oncology", "Basic cancer research", "Tumor physiology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "promoter", "methylation", "marks", "hcc", "cells", "exposed"], "article_id"=>921791, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Alejandra Ward", "John W. Hudson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087918.g004", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Modification_of_PLK_promoter_methylation_marks_in_HCC_cells_exposed_to_ROS_/921791", "title"=>"Modification of <i>PLK</i> promoter methylation marks in HCC cells exposed to ROS.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 02:47:32"}

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Relative Metric

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