FOXM1 Induces a Global Methylation Signature That Mimics the Cancer Epigenome in Head and Neck Squamous Cell Carcinoma
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{"title"=>"Foxm1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma", "type"=>"journal", "authors"=>[{"first_name"=>"Muy Teck", "last_name"=>"Teh", "scopus_author_id"=>"7003510239"}, {"first_name"=>"Emilios", "last_name"=>"Gemenetzidis", "scopus_author_id"=>"26421722800"}, {"first_name"=>"Deeviyaben", "last_name"=>"Patel", "scopus_author_id"=>"55131055900"}, {"first_name"=>"Rameez", "last_name"=>"Tariq", "scopus_author_id"=>"55131611500"}, {"first_name"=>"Ayesha", "last_name"=>"Nadir", "scopus_author_id"=>"55133909900"}, {"first_name"=>"Adiam W.", "last_name"=>"Bahta", "scopus_author_id"=>"21233707300"}, {"first_name"=>"Ahmad", "last_name"=>"Waseem", "scopus_author_id"=>"7003450641"}, {"first_name"=>"Iain L.", "last_name"=>"Hutchison", "scopus_author_id"=>"7003795118"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84858831140", "pmid"=>"22461910", "isbn"=>"0311588700", "pui"=>"364505206", "issn"=>"19326203", "scopus"=>"2-s2.0-84858831140", "doi"=>"10.1371/journal.pone.0034329"}, "id"=>"50d22bd9-b3d6-30e1-af4e-a49aa343c411", "abstract"=>"The oncogene FOXM1 has been implicated in all major types of human cancer. We recently showed that aberrant FOXM1 expression causes stem cell compartment expansion resulting in the initiation of hyperplasia. We have previously shown that FOXM1 regulates HELLS, a SNF2/helicase involved in DNA methylation, implicating FOXM1 in epigenetic regulation. Here, we have demonstrated using primary normal human oral keratinocytes (NOK) that upregulation of FOXM1 suppressed the tumour suppressor gene p16(INK4A) (CDKN2A) through promoter hypermethylation. Knockdown of HELLS using siRNA re-activated the mRNA expression of p16(INK4A) and concomitant downregulation of two DNA methyltransferases DNMT1 and DNMT3B. The dose-dependent upregulation of endogenous FOXM1 (isoform B) expression during tumour progression across a panel of normal primary NOK strains (n = 8), dysplasias (n = 5) and head and neck squamous cell carcinoma (HNSCC) cell lines (n = 11) correlated positively with endogenous expressions of HELLS, BMI1, DNMT1 and DNMT3B and negatively with p16(INK4A) and involucrin. Bisulfite modification and methylation-specific promoter analysis using absolute quantitative PCR (MS-qPCR) showed that upregulation of FOXM1 significantly induced p16(INK4A) promoter hypermethylation (10-fold, P<0.05) in primary NOK cells. Using a non-bias genome-wide promoter methylation microarray profiling method, we revealed that aberrant FOXM1 expression in primary NOK induced a global hypomethylation pattern similar to that found in an HNSCC (SCC15) cell line. Following validation experiments using absolute qPCR, we have identified a set of differentially methylated genes, found to be inversely correlated with in vivo mRNA expression levels of clinical HNSCC tumour biopsy samples. This study provided the first evidence, using primary normal human cells and tumour tissues, that aberrant upregulation of FOXM1 orchestrated a DNA methylation signature that mimics the cancer methylome landscape, from which we have identified a unique FOXM1-induced epigenetic signature which may have clinical translational potentials as biomarkers for early cancer screening, diagnostic and/or therapeutic interventions.", "link"=>"http://www.mendeley.com/research/foxm1-induces-global-methylation-signature-mimics-cancer-epigenome-head-neck-squamous-cell-carcinoma", "reader_count"=>61, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Librarian"=>1, "Researcher"=>12, "Student > Doctoral Student"=>6, "Student > Ph. D. Student"=>20, "Student > Postgraduate"=>5, "Other"=>2, "Student > Master"=>3, "Student > Bachelor"=>6, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Librarian"=>1, "Researcher"=>12, "Student > Doctoral Student"=>6, "Student > Ph. D. Student"=>20, "Student > Postgraduate"=>5, "Other"=>2, "Student > Master"=>3, "Student > Bachelor"=>6, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>4, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>30, "Medicine and Dentistry"=>11, "Business, Management and Accounting"=>1, "Chemistry"=>3, "Psychology"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Chemistry"=>{"Chemistry"=>3}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>30}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Unspecified"=>{"Unspecified"=>4}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Denmark"=>2, "Italy"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/663427"], "description"=>"<p>(<b>A</b>) FOXM1 significantly supresses <i>p16<sup>INK4A</sup></i> mRNA and protein expression (inset figure) in primary normal human keratinocytes. GAPDH was used as a control for protein loading. Control cells (mock-transduced with empty retroviral particles or EGFP-transduced) did not show significant suppression of p16<sup>INK4A</sup> expression. (<b>B</b>) Knockdown of a FOXM1-target gene <i>HELLS</i>, which regulates genome-wide methylation <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034329#pone.0034329-Dennis1\" target=\"_blank\">[14]</a>, induced <i>p16<sup>INK4A</sup></i> and simultaneously suppressed <i>DNMT1</i> and <i>DNMT3B</i>, but not <i>DNMT3A</i> mRNA expression in a FOXM1-transformed malignant cell line (SVFN5) expressing constitutive levels of endogenous <i>HELLS </i><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034329#pone.0034329-Gemenetzidis1\" target=\"_blank\">[8]</a>. Each bar represents a mean ± SEM of triplicate transfection (48 h) with either siCTRL or siHELLS. *P<0.05, **P<0.01 and ***P<0.001 indicate the level of statistical significance compared to controls. (<b>C</b>) Endogenous <i>FOXM1</i> (isoform B) mRNA expression levels in 8 strains of primary human normal oral keratinocytes, 5 dysplastic and 11 HNSCC cell lines. Total <i>FOXM1</i> mRNA expression levels were measured in the EGFP and FOXM1-transduced NOK (NOKG and NOKF), respectively. (<b>D</b>–<b>J</b>) Third-order polynomial regression analyses were performed to obtain the R<sup>2</sup> coefficient of determination values which indicate the significance of co-expression between each gene with <i>FOXM1</i> across the 24 cell strains/lines indicated in panel C.</p>", "links"=>[], "tags"=>["foxm1", "suppressed"], "article_id"=>333906, "categories"=>["Cancer", "Genetics"], "users"=>["Muy-Teck Teh", "Emilios Gemenetzidis", "Deeviyaben Patel", "Rameez Tariq", "Ayesha Nadir", "Adiam W. Bahta", "Ahmad Waseem", "Iain L. Hutchison"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034329.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Upregulation_of_FOXM1_suppressed_p16_INK4A_expression_in_primary_human_oral_keratinocytes_/333906", "title"=>"Upregulation of FOXM1 suppressed <i>p16<sup>INK4A</sup></i> expression in primary human oral keratinocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-03-26 01:05:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/340914"], "description"=>"<div><p>The oncogene FOXM1 has been implicated in all major types of human cancer. We recently showed that aberrant FOXM1 expression causes stem cell compartment expansion resulting in the initiation of hyperplasia. We have previously shown that FOXM1 regulates <em>HELLS</em>, a SNF2/helicase involved in DNA methylation, implicating <em>FOXM1</em> in epigenetic regulation. Here, we have demonstrated using primary normal human oral keratinocytes (NOK) that upregulation of <em>FOXM1</em> suppressed the tumour suppressor gene <em>p16<sup>INK4A</sup></em> (<em>CDKN2A</em>) through promoter hypermethylation. Knockdown of <em>HELLS</em> using siRNA re-activated the mRNA expression of <em>p16<sup>INK4A</sup></em> and concomitant downregulation of two DNA methyltransferases <em>DNMT1</em> and <em>DNMT3B</em>. The dose-dependent upregulation of endogenous <em>FOXM1</em> (isoform B) expression during tumour progression across a panel of normal primary NOK strains (n = 8), dysplasias (n = 5) and head and neck squamous cell carcinoma (HNSCC) cell lines (n = 11) correlated positively with endogenous expressions of <em>HELLS</em>, <em>BMI1</em>, <em>DNMT1</em> and <em>DNMT3B</em> and negatively with <em>p16<sup>INK4A</sup></em> and involucrin. Bisulfite modification and methylation-specific promoter analysis using absolute quantitative PCR (MS-qPCR) showed that upregulation of <em>FOXM1</em> significantly induced <em>p16<sup>INK4A</sup></em> promoter hypermethylation (10-fold, P<0.05) in primary NOK cells. Using a non-bias genome-wide promoter methylation microarray profiling method, we revealed that aberrant <em>FOXM1</em> expression in primary NOK induced a global hypomethylation pattern similar to that found in an HNSCC (SCC15) cell line. Following validation experiments using absolute qPCR, we have identified a set of differentially methylated genes, found to be inversely correlated with <em>in vivo</em> mRNA expression levels of clinical HNSCC tumour biopsy samples. This study provided the first evidence, using primary normal human cells and tumour tissues, that aberrant upregulation of <em>FOXM1</em> orchestrated a DNA methylation signature that mimics the cancer methylome landscape, from which we have identified a unique <em>FOXM1</em>-induced epigenetic signature which may have clinical translational potentials as biomarkers for early cancer screening, diagnostic and/or therapeutic interventions.</p> </div>", "links"=>[], "tags"=>["foxm1", "induces", "methylation", "mimics", "cancer", "epigenome", "squamous", "carcinoma"], "article_id"=>127388, "categories"=>["Cancer", "Genetics"], "users"=>["Muy-Teck Teh", "Emilios Gemenetzidis", "Deeviyaben Patel", "Rameez Tariq", "Ayesha Nadir", "Adiam W. Bahta", "Ahmad Waseem", "Iain L. Hutchison"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034329", "stats"=>{"downloads"=>6, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/FOXM1_Induces_a_Global_Methylation_Signature_That_Mimics_the_Cancer_Epigenome_in_Head_and_Neck_Squamous_Cell_Carcinoma/127388", "title"=>"FOXM1 Induces a Global Methylation Signature That Mimics the Cancer Epigenome in Head and Neck Squamous Cell Carcinoma", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-03-26 02:03:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/663662"], "description"=>"<p>(<b>A</b>) Bisulfite modification and methylation specific absolute qPCR for the quantification of <i>p16<sup>INK4A</sup></i> promoter methylation status. Genomic DNA was first treated with sodium bisulfite prior to PCR pre-amplification of the promoter region of <i>p16<sup>INK4A</sup></i> (PCR<sup>BS</sup>, 273 bp). Methylation specific (p16M-R/F) and methylation-independent (p16U-F/R) primers were then used to quantify the relative levels of methylated and unmethylated products within the PCR<sup>BS</sup> sample using standard-curve based absolute qPCR method for each product, respectively. Melting analysis was performed to validate the qPCR specificity in detecting the two M and U products. (<b>B</b>) Bisulfite conversion and methylation specific qPCR were performed to measure the relative levels of unmethylated (U, melting temperature at 85.8°C) and methylated (M, 91.2°C) in either EGFP- or FOXM1-transduced primary NOK treated with either vehicle (DMSO) or 5Aza (1 µM, 3-day incubation with fresh drug replenishment daily). A total of n = 11 replicates from at least 4 independent experiments were performed. Statistical t-test significance notations *P<0.05 and ***P<0.001.</p>", "links"=>[], "tags"=>["induces", "promoter", "hypermethylation"], "article_id"=>334146, "categories"=>["Cancer", "Genetics"], "users"=>["Muy-Teck Teh", "Emilios Gemenetzidis", "Deeviyaben Patel", "Rameez Tariq", "Ayesha Nadir", "Adiam W. Bahta", "Ahmad Waseem", "Iain L. Hutchison"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034329.g002", "stats"=>{"downloads"=>0, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FOXM1_induces_promoter_hypermethylation_of_p16_INK4A_gene_in_primary_human_oral_keratinocytes_/334146", "title"=>"<i>FOXM1</i> induces promoter hypermethylation of <i>p16<sup>INK4A</sup></i> gene in primary human oral keratinocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-03-26 01:09:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/663806"], "description"=>"<p>(<b>A</b>) Genome-wide promoter microarray analysis of primary normal oral human keratinocytes expressing either <i>EGFP</i> (NOKG, black dots) or <i>FOXM1</i> (NOKF, yellow dots) and an established squamous cell carcinoma cell line (SCC15, red dots). Each dot represents a single gene. (<b>B</b>) A non-linear 2<sup>nd</sup> order polynomial regression analyses were performed on the relative methylation patterns between NOKG vs NOKF (inverse correlation), NOKG vs SCC15 (inverse correlation) and NOKF vs SCC15 (positive correlation). (<b>C</b>) Gene selection criteria for differentially methylated genes between control (NOKG) and tests groups (NOKF and SCC15). 100-most hypermethylated and 100-most hypomethylated genes were inversely matched with differentially methylated genes from NOKF and SCC15. The adjacent gene lists show the shortlisted FOXM1-induced (also found in SCC15) differentially hypermethylated (red) and hypomethylated (green) genes compared to control NOKG cells. The CDKN2A (encodes <i>p16<sup>INK4A</sup></i>) gene, its promoter known to be hypermethylated in HNSCC, was included as a positive control for promoter hypermethylation. (<b>D</b>) Clinical tumour tissue sample correlation between the relative levels of methylation and gene expression of each shortlisted gene in a cohort of 10 patients with paired normal margin and HNSCC tumour tissue samples. Each dot represents mean ± SEM of each gene. Vertical error bars were derived from relative gene expression of 10 margin-tumour tissue pairs and horizontal error bars were derived from relative promoter methylation of 3 independent primary NOK (NOKG/NOKF) experiments. Correlation coefficient (R<sup>2</sup>) of a non-linear 2<sup>nd</sup> order polynomial regression analyses were performed on all 30 candidate genes (left panel), 16 hypermethylated genes (middle panel) or 14 hypomethylated genes (right panel), respectively.</p>", "links"=>[], "tags"=>["induces", "methylation", "mimics", "cancer"], "article_id"=>334285, "categories"=>["Cancer", "Genetics"], "users"=>["Muy-Teck Teh", "Emilios Gemenetzidis", "Deeviyaben Patel", "Rameez Tariq", "Ayesha Nadir", "Adiam W. Bahta", "Ahmad Waseem", "Iain L. Hutchison"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034329.g003", "stats"=>{"downloads"=>2, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Upregulation_of_FOXM1_isoform_B_induces_a_global_shift_in_methylation_pattern_that_mimics_the_cancer_epigenome_/334285", "title"=>"Upregulation of <i>FOXM1</i> (isoform B) induces a global shift in methylation pattern that mimics the cancer epigenome.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-03-26 01:11:25"}

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Relative Metric

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