The association between Histone 3 Lysine 27 Trimethylation (H3K27me3) and prostate cancer: relationship with clinicopathological parameters

BMC Cancer

Marjolaine Ngollo³  Andre Lebert⁴  Aslihan Dagdemir³  Gaelle Judes³  Seher Karsli-Ceppioglu³  Marine Daures³  Jean-Louis Kemeny²  Frederique Penault-Llorca³  Jean-Paul Boiteux¹  Yves-Jean Bignon³  Laurent Guy¹  Dominique Bernard-Gallon³ 

[1] Department of Urology, Gabriel Montpied Hospital, 58 rue Montalembert, 63001 Clermont-Ferrand, France

[2] Department of Anatomo-pathology, Gabriel Montpied Hospital, 58 rue Montalembert, 63001 Clermont-Ferrand, France

[3] EA 4677 "ERTICA", University of Auvergne, 28 place Henri Dunant, BP 38, 63001 Clermont-Ferrand, France

[4] University Blaise Pascal, Institut Pascal UMR 6602 CNRS/UBP, 24 Avenue des Landais, Aubiere, France

关键词: Trimethylation;    Histone modifications;    Prostate cancer;    Epigenetic;    Chromatin immunoprecipitation;   

Others  :  1106783
DOI  :  10.1186/1471-2407-14-994

 received in 2014-08-20, accepted in 2014-12-16,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Ngollo et al.; licensee BioMed Central.

【 图 表 】

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