title: The association between histone 3 lysine 27 trimethylation (H3K27me3) and prostate cancer: relationship with clinicopathological parameters.
abstract: BACKGROUND
  It is well established that genetic and epigenetic alterations are common events in prostate cancer, which may lead to aberrant expression of critical genes. The importance of epigenetic mechanisms in prostate cancer carcinogenesis is increasingly evident. In this study, the focus will be on histone modifications and the primary objectives are to map H3K27me3 marks and quantify RAR beta 2, ER alpha, SRC3, RGMA, PGR, and EZH2 gene expressions in prostate cancer tissues compared to normal tissues. In addition, a data analysis was made in connection with the clinicopathological parameters.
  
  
  METHODS
  71 normal specimens and 66 cancer prostate tissues were randomly selected in order to assess the proportion of the repressive H3K27me3 mark and gene expression. H3K27me3 level was evaluated by ChIP-qPCR and mRNA expression using RT-qPCR between prostate cancer and normal tissues. Subsequently, western-blotting was performed for protein detection. The analysis of variance (ANOVA) was performed, and Tukey's test was used to correct for multiple comparisons (p-value threshold of 0.05). The principal component analysis (PCA) and discriminant factorial analysis (DFA) were used to explore the association between H3K27me3 level and clinicopathological parameters.
  
  
  RESULTS
  The study demonstrated that H3K27me3 level was significantly enriched at the RAR beta 2, ER alpha, PGR, and RGMA promoter regions in prostate cancer tissues compared to normal tissues. After stratification by clinicopathological parameters, the H3K27me3 level was positively correlated with Gleason score, PSA levels and clinical stages for RAR beta 2, ER alpha, PGR, and RGMA. High H3K27me3 mark was significantly associated with decreased RAR beta 2, ER alpha, PGR and RGMA gene expressions in prostate cancer sample compared to the normal one. Moreover, the results showed that mRNA level of EZH2, AR and SRC3 are upregulated in prostate cancer compared to normal prostate tissues and this correlates positively with Gleason score, PSA levels and clinical stages. Obviously, these observations were confirmed by protein level using western-blot.
  
  
  CONCLUSIONS
  This data clearly demonstrated that H3K27me3 level correlated with aggressive tumor features. Also this study revealed that reverse correlation of RAR beta 2, ER alpha, PGR, and RGMA expressions with EZH2, SRC3, and AR expressions in prostate cancer tissues suggests that these genes are the target of EZH2. Therefore, all therapeutic strategies leading to histone demethylation with epigenetic drugs such as histone methyltransferase inhibitor may be relevant treatments against prostate cancer.
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Ngollo
authors.forename: Andre
authors.initials: A
authors.lastname: Lebert
authors.forename: Aslihan
authors.initials: A
authors.lastname: Dagdemir
authors.forename: Gaelle
authors.initials: G
authors.lastname: Judes
authors.forename: Seher
authors.initials: S
authors.lastname: Karsli-Ceppioglu
authors.forename: Marine
authors.initials: M
authors.lastname: Daures
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kemeny
authors.forename: Frederique
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Boiteux
authors.affiliation: Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri Dunant, BP 38, 63001 Clermont-Ferrand, France. Yves-Jean.BIGNON@cjp.fr.
authors.forename: Yves-Jean
authors.initials: YJ
authors.lastname: Bignon
authors.forename: Laurent
authors.initials: L
authors.lastname: Guy
authors.forename: Dominique
authors.initials: D
authors.lastname: Bernard-Gallon
mesh_terms: D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics*; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D025341:Principal Component Analysis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics
chemical_list: C410798:AR protein, human; D006657:Histones; C533416:RARB2 protein, human; D011944:Receptors, Androgen; D018168:Receptors, Retinoic Acid; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3