High EZH2 expression is correlated to metastatic disease in pediatric soft tissue sarcomas

Abstract

BackgroundEnhancer of Zeste Drosophila Homologue 2 (EZH2) is a key regulator of transcription as a member of polycomb repressive complex 2 (PRC2) which exerts repression of downstream genes and is correlated to invasiveness and progression of different tumours. Therefore, we evaluated the expression of PRC2 proteins in pediatric soft tissue sarcoma (rhabdomyosarcoma, RMS and extraosseous Ewing sarcoma, EES) correlating them to the clinical outcome of the patients.MethodsWe analyzed PRC2 protein expression by quantitative real time PCR, western blotting and immunohistochemistry in 17 soft tissue sarcomas (11 RMS and 6 EES) enrolled at Paediatric Oncology Units of the Second University of Naples. Expression analysis was performed for EZH2, SUZ12 and EED.ResultsEnhancer of Zeste Drosophila Homologue 2 was expressed with a different degree in 60 % of samples. Interestingly, the magnitude of EZH2 up regulation was significantly higher in patients presenting lymph node and/or distant metastases at the diagnosis. Moreover, patients overexpressing EZH2 had a lower probability of survival compared to patients negative or with low EZH2 expression.ConclusionsOur study suggests that high EZH2 expression is associated to increased aggressiveness of the disease. Therefore, drugs that control its activity could be potentially used in the epigenetic target treatment of tumors with these alterations.

Polycomb repressive 2 complex—Molecular mechanisms of function

“…Further studies are needed to ensure that it does not interfere with other vital molecular processes . Ramaglia and colleagues suggested approaching with caution to possible extensive usage of DZNep in myeloid neoplasms, also stressing the importance of additional studies . A common theme between other inhibitors is the pyridine group .…”

“…The molecular mechanisms that cause the overexpression of EZH2, and the malignant effects that accompany it are also important for evaluating potential biomarkers. Proteins such as EWS/FL11, E2F1, and MYC have all been shown to induce EZH2 expression while cyclin‐dependent kinase 1/2 has been shown to stimulate it . One study shows that the long coding RNA ROR1‐AS1 interacts with the PRC2 complex through the EZH2 protein and that inhibition of EZH2 abolishes this interaction.…”

High expression of EZH2 as a marker for the differential diagnosis of malignant and benign myogenic tumors

“…Ewing sarcoma and RMS are common pediatric sarcomas with high malignance. Ramaglia 10 found that EZH2 was expressed with a different degree in 60% of 17 patients with Ewing sarcoma or RMS and it was significantly higher in patients presenting lymph node and/or distant metastases. Moreover, overexpression of EZH2 was positively relative to lower probability of survival.…”

The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma

“…2,3 Recent studies have shown that, in both ERMS and ARMS, epigenetic dysregulation plays a role in inhibition of terminal myogenic differentiation, and in promotion of proliferative, invasive, and metastatic phenotypes. [4][5][6][7] Genome-wide profiling of DNA methylation in RMS has shown that, while there are common epigenetic aberrations among ERMS and ARMS, they also have distinct epigenetic profiles. [8][9][10] Specifically, fusion-positive (ARMS) tumors showed global decreased methylation when compared to ERMS tumors, with higher frequency of CpG sites that had low methylation, and a lower frequency of CpG that had higher methylation levels.…”