Deregulation of EZH2 expression in human spermatogenic disorders and testicular germ cell tumors

Hinz, Stefan; Magheli, Ahmed; Weikert, Steffen; Schulze, Wolfgang; Krause, Hans; Schrader, Mark; Miller, Kurt; Kempkensteffen, Carsten

doi:10.1007/s00345-009-0498-6

Cited by 23 publications

(13 citation statements)

References 19 publications

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“…This is due to lower levels of DNA methylation and of histone methylation (H3K9me2 and H3K27me3; Almstrup et al, 2010). This is consistent with a lower expression of the gene encoding for the EZH2 in the TGCC compared to normal testis tissues (Hinz et al, 2010). This suggests that in TGCC EZH2 does not exert its often assumed oncogenic properties during malignant transformation and progression.…”

Section: Epigenetic and Testicular Cancerssupporting

confidence: 82%

Epigenetic: a molecular link between testicular cancer and environmental exposures

Véga¹,

Baptissart²,

Caira³

et al. 2012

Front. Endocrin.

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In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the testicular dysgenesis syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Furthermore, infertility has been stated as a risk factor for testicular cancer (TC). The incidence of TC has been increasing over the past decade. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ from fetal germ cells (primordial germ cell or gonocyte). During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications) plays an important role in normal development as well as in various diseases, including TC. Here we will review chromatin modifications which can affect testicular physiology leading to the development of TC; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures.

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Section: Epigenetic and Testicular Cancerssupporting

confidence: 82%

Epigenetic: a molecular link between testicular cancer and environmental exposures

Véga¹,

Baptissart²,

Caira³

et al. 2012

Front. Endocrin.

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“…Quantitative meiotic splicing regulation also takes place in other genes implicated in key roles in germ cell development. The Ezh2 gene encodes an important chromatin modifier that can affect development (80) and might play an important role in normal fertility (81,82). A mutually exclusive exon is selected in the Ate1 gene, and the meiotic Ate1 mRNA isoform is the major mRNA made from this gene in the mouse testis (Supplementary File S1).…”

Section: Discussionmentioning

confidence: 99%

The splicing landscape is globally reprogrammed during male meiosis

Schmid¹,

Grellscheid²,

Ehrmann³

et al. 2013

Nucleic Acids Research

103

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Meiosis requires conserved transcriptional changes, but it is not known whether there is a corresponding set of RNA splicing switches. Here, we used RNAseq of mouse testis to identify changes associated with the progression from mitotic spermatogonia to meiotic spermatocytes. We identified ∼150 splicing switches, most of which affect conserved protein-coding exons. The expression of many key splicing regulators changed in the course of meiosis, including downregulation of polypyrimidine tract binding protein (PTBP1) and heterogeneous nuclear RNP A1, and upregulation of nPTB, Tra2β, muscleblind, CELF proteins, Sam68 and T-STAR. The sequences near the regulated exons were significantly enriched in target sites for PTB, Tra2β and STAR proteins. Reporter minigene experiments investigating representative exons in transfected cells showed that PTB binding sites were critical for splicing of a cassette exon in the Ralgps2 mRNA and a shift in alternative 5′ splice site usage in the Bptf mRNA. We speculate that nPTB might functionally replace PTBP1 during meiosis for some target exons, with changes in the expression of other splicing factors helping to establish meiotic splicing patterns. Our data suggest that there are substantial changes in the determinants and patterns of alternative splicing in the mitotic-to-meiotic transition of the germ cell cycle.

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“…The only reported exception of downregulation of EZH2 in human carcinoma was observed in testicular germ cell tumors, in which a decreased EZH2 mRNA was detected in seminoma and nonseminoma tumor compared to normal testicular parenchyma. 95 Using quantitative real-time polymerase chain reaction (qRT-PCR) or immunohistochemistry, only 3 previous studies [61][62][63] have reported a similar increase of EZH2 in RCC. Table 5 shows a detailed summary of all published studies reporting the association of EZH2 at the protein level with the tumor's clinicopathologic characteristics and outcome in carcinomas of different organs.…”

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confidence: 99%

Enhancer of Zeste Homolog 2 Expression Is Associated With Metastasis and Adverse Clinical Outcome in Clear Cell Renal Cell Carcinoma: A Comparative Study and Review of the Literature

Abourbih

Sircar

et al. 2013

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase mediating chromatin condensation and epigenetic modulation, is overexpressed in various human carcinomas and is associated with adverse clinicopathologic characteristics and biologic behavior. The expression of EZH2 in renal cell carcinomas (RCCs) has not been fully characterized yet.Objective.-To evaluate the prognostic role of EZH2 in RCC by analyzing the immunohistochemical staining pattern of the marker in relation to pathologic features and clinical outcome.Design.-We correlated the immunolabeling of EZH2 with multiple clinicopathologic features, including Fuhrman nuclear grade, pathologic stage, metastatic status, and clinical outcome in 223 clear cell RCCs (CRCCs) and 21 papillary RCCs, by using tissue microarrays of primary and metastatic cases.Results.-Most CRCCs (75%) showed positive EZH2 staining, with most primary tumors showing focal staining in comparison to nonfocal staining in metastatic cases. In primary tumors, EZH2 expression was associated with higher nuclear grade and lower pathologic stage. Metastatic tumors showed a higher number of positive cases (81% versus 67%) and a more diffuse and more intense pattern of staining than primary CRCCs. For the 22 locally advanced primary tumors (T3/4) and 43 metastatic RCCs, patients who experienced RCC-related deaths significantly overexpressed the marker in comparison to patients who did not experience RCC-related mortality.Conclusions.-By showing that EZH2 expression is associated with increased metastatic potential and a worse clinical outcome, this study suggests that EZH2 can serve as a prognostic biomarker for RCC, thus confirming it as a key molecule driving oncogenesis and metastasis.

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Deregulation of EZH2 expression in human spermatogenic disorders and testicular germ cell tumors

Cited by 23 publications

References 19 publications

Epigenetic: a molecular link between testicular cancer and environmental exposures

Epigenetic: a molecular link between testicular cancer and environmental exposures

The splicing landscape is globally reprogrammed during male meiosis

Enhancer of Zeste Homolog 2 Expression Is Associated With Metastasis and Adverse Clinical Outcome in Clear Cell Renal Cell Carcinoma: A Comparative Study and Review of the Literature

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