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

Ngollo, Marjolaine; Lebert, André; Dagdemir, Aslihan; Judes, Gaëlle; Karslı-Çeppioğlu, Seher; Daures, Marine; Kémény, Jean-Louis; Penault‐Llorca, Frédérique; Boiteux, Jean‐Paul; Bignon, Yves‐Jean; Guy, Laurent; Bernard‐Gallon, Dominique

doi:10.1186/1471-2407-14-994

Cited by 47 publications

(34 citation statements)

References 41 publications

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“…2 That study provided a clue on the role of SKP2 on histone modifications and the epigenetic alterations in PCa. Although levels of SKP2 and Enhancer of zeste homolog 2 (EZH2) are highly associated with aggressive features of human PCa, 1,14 it remains unclear whether SKP2 determines the levels of histone H3 lysine 27 trimethylation (H3K27me3) state by modulating EZH2.…”

Section: Introductionmentioning

confidence: 99%

SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer

Liu

et al. 2016

Oncogene

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EZH2 is crucial for the progression of prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) through upregulation and activation of progenitor genes, as well as androgen receptor (AR)-target genes. However, the mechanisms by which EZH2 is regulated in PCa and CRPC remain elusive. Here we report that EZH2 is post-transcriptionally regulated by SKP2 in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of Skp2, Ezh2 and histone H3 lysine 27 trimethylation (H3K27me3) in both Pten null mouse embryonic fibroblasts (MEFs) and Pten null mouse prostate tissues. Loss of Skp2 resulted in a striking decrease of Ezh2 levels in Pten/Trp53 double-null MEFs and in prostate tumors of Pten/Trp53 double-null mutant mice. SKP2 knockdown decreased EZH2 levels in human PCa cells through upregulation of TRAF6-mediated and lysine(K) 63-linked ubiquitination of EZH2 for degradation. Ectopic expression of TRAF6 promoted the K63-linked ubiquitination of EZH2 to decrease EZH2 and H3K27me3 levels in PCa cells. In contrast, TRAF6 knockdown resulted in a reduced EZH2 ubiquitination with an increase of EZH2 and H3K27me3 levels in PCa cells. Furthermore, the catalytically dead mutant TRAF6 C70A abolished the TRAF6-mediated polyubiquitination of recombinant human EZH2 in vitro. Most importantly, a concurrent elevation of Skp2 and Ezh2 was found in CRPC tumors of Pten/Trp53 mutant mice, and expression levels of SKP2 and EZH2 were positively correlated in human PCa specimens. Taken together, our findings revealed a novel mechanism on EZH2 ubiquitination and an important signaling network of SKP2-TRAF6-EZH2/H3K27me3, and targeting SKP2-EZH2 pathway may be a promising therapeutic strategy for CRPC treatment.

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Section: Introductionmentioning

confidence: 99%

SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer

Liu

et al. 2016

Oncogene

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“…Enhancer of zeste 2 polycomb repressive complex 2 subunit, a methyl-transferase for H3K27, is upregulated in a variety of tumors and serves an essential role in tumor promotion (2,16); our previous study reached the same conclusion (17). Certain studies have widely associated H3K27me3 with gene silencing and transcriptional inhibition (6,18); however, these studies have not achieved a consensus on the level of H3K27me3 and the significance of its aberrant expression in human tumorigenesis. Previous studies have suggested that the low expression level of H3K27me3 in tumor tissues may enhance the expression of oncogenes and consequently promote tumor growth (19)(20)(21)(22); however, Nakazawa et al (23) revealed no significant differences when comparing the expression levels of H3K4me2 and H3K27me3 in 85 cases of colorectal cancer with the paired normal colorectal tissues.…”

Section: Discussionmentioning

confidence: 75%

The expression and significance of histone lysine methylation in endometrial cancer

Nan

Tao

et al. 2017

Oncol Lett

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Abstract. Histone modifications of lysine residues have been implicated as having diagnostic and/or prognostic significance in numerous types of cancer. In the present study, the significance of the histone H3 methylation of lysine 4 (H3K4) and lysine 27 (H3K27) were investigated in endometrial cancer. Specifically, immunohistochemical analysis was used to detect the cellular expression levels of H3K27 trimethylation (H3K27me3), H3K4 trimethylation (H3K4me3) and H3K4 dimethylation (H3K4me2) in glandular epithelial tissues and stromal tissues. The association between the methylation levels of histone markers and clinicopathological parameters were analyzed. The results demonstrated that in epithelial cells, H3K4me2 and H3K4me3 exhibited the highest levels in endometrial cancer, followed by precancerous lesions and a normal endometrium. Low expression levels of H3K4me2 in glandular epithelium of endometrial cancer were significantly associated with a clinical early International Federation of Gynecology and Obstetrics stage (P= 0.006). For stromal tissues, the expression level of H3K27me3 in Type 1 endometrial cancer was significantly lower compared with that in the normal endometrium (P= 0.043) and precancerous lesions (P<0.001). The expression level of H3K4me2 was significantly lower in the stroma of Type 1 and 2 cancer compared within the normal endometrium (P= 0.005). A low H3K4me3 expression level in the stroma of endometrial cancer tissues was associated with P53-negativity (P= 0.032). In conclusion, the cellular expression levels of histone H3 methylation were differentially presented in glandular epithelial and stromal elements in endometrial tissues. A low expression level of activation marker H3K4me2 in glandular epithelium defined a subset of patients with early-stage endometrial adenocarcinoma and may have potential prognostic value.

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“…1B). AR mRNAs were evaluated by reverse transcriptase (RT)-quantitative polymerase chain reaction (Q-PCR) (Ngollo et al, 2014) as shown in Figure 2A and were found highly expressed in the LAR subtype compared with the basal-like subtypes with a significant difference ( p = 0.029).Therefore, H3 modifications on AR promoter gene were studied in LAR and basal-like subtypes by immunoprecipitation of chromatin (Dagdemir et al, 2013;Ngollo et al, 2014) following by Q-PCR (Fig. 2B).…”

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Molecular and Epigenetic Biomarkers in Luminal Androgen Receptor: A Triple Negative Breast Cancer Subtype

Judes

Dagdemir

Karslı-Çeppioğlu

et al. 2016

OMICS: A Journal of Integrative Biology

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Recently, Lehmann et al. (2011) identified six different subtypes of triple negative breast cancer (TNBC) according to the gene expression profiles, including a luminal androgen receptor (LAR) subtype. The LAR subtype was notable by differences in androgen receptor (AR) signaling and luminal cytokeratin expression. Therefore, TNBC subtype is anticipated to be a highly heterogeneous group; the molecular understanding of this breast cancer type is critical to develop innovative and effective drugs. Moreover, the subtyping of TNBC is essential to better identify molecular biomarkers, and epigenetic understanding can contribute to this challenge.In a previous study, we have observed a decrease in H3K27me3 and H3K9me3 markers with BRCA1, EZH2, and ER-a genes in tumor breast cell lines (MDA-MB-231 and MCF7) treated with 17b-estradiol and soybean phytoestrogens and an increase in H4K8ac and H3K4ac markers with these genes following suberoylanilide hydroxamic acid (SAHA) (Dagdemir et al., 2013). These epigenetic modifications have responded to different treatments and have been able to mediate silencing or enhancing genes. Thereafter, a high variability in H3 modifications (H3K27me3, H3K9ac, and H3K4ac) on a promoter gene panel (BRCA1, EZH2, P300, SCR3, ERS1, ERS2, and PGR) implicated in breast cancer was found within the TNBC subtype (Judes et al., 2016). In view of these results, we studied AR expression by immunohistochemistry (IHC) in these tumors and established a correlation with their epigenetic profile.IHC was performed for 34 TNBCs, including those with positive nuclear staining for AR (n = 12) and presented an extensive staining for luminal markers (CK8/18 and CK19). The other groups presented a negative staining for AR (n = 22), displaying an expression of luminal markers and a notable staining for basal markers like CK5/6. Moreover, in the ARgroup, 95.45% presented a Ki67 ‡ 20% compared with the AR + group where 58.33% presented a 14% < Ki67 < 19%.Collectively, we report here the presence of two groups (AR + and AR -) inside the TNBC studied tumors. In Figure 1A, for AR + tumors (n = 12), the staining significantly increased in CK8/18 ( p = 0.02) and CK19 ( p = 0.01) compared with ARtumors (n = 22). CK5/6 and Ki67 were found significantly decreased ( p = 0.02; p = 1.63 · 10 -7 ) in the AR + group in comparison with the AR -group. Among the studied TNBCs, a part of them was distinguished with higher AR expression, reduced proliferation, and strongly expressed luminal cytokeratins. This subtype is called LAR that was also characterized by ER -and PGR -, negative CK5/6 expression (Fig. 1B). AR mRNAs were evaluated by reverse transcriptase (RT)-quantitative polymerase chain reaction (Q-PCR) (Ngollo et al., 2014) as shown in Figure 2A and were found highly expressed in the LAR subtype compared with the basal-like subtypes with a significant difference ( p = 0.029).Therefore, H3 modifications on AR promoter gene were studied in LAR and basal-like subtypes by immunoprecipitation of chromatin (Dagdemir et al., 2013;N...

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

Cited by 47 publications

References 41 publications

SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer

SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer

The expression and significance of histone lysine methylation in endometrial cancer

Molecular and Epigenetic Biomarkers in Luminal Androgen Receptor: A Triple Negative Breast Cancer Subtype

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