Inibição de G9a como um potencial alvo terapêutico : uma avaliação em tumores pediátricos

Tumores pediátricos são considerados neoplasias raras, apesar disso, são vistas como a segunda maior causa de óbito em pacientes pediátricos. Em conjunto, os tumores meduloblastoma, neuroblastoma e sarcoma de Ewing, são responsáveis por mais de 30% dos casos de neoplasias pediátricas. Mecanismos epigenéticos têm sido considerados importantes para o desenvolvimento e progressão tumoral, dessa forma, o presente estudo buscou explorar o papel da histona metiltransferase G9a em processos celulares relevantes para o desenvolvimento das neoplasias pediátricas meduloblastoma, neuroblastoma e sarcoma de Ewing. Os resultados obtidos sugerem que existe uma associação entre os níveis de G9a e a tumorgenicidade desses tumores. Além disso, foi encontrado que inibição da atividade de G9a e a alteração dos níveis de dimetilação de H3K9 estão envolvidos na manutenção da viabilidade celular, na expressão de genes supressores tumorais e na capacidade de sobrevivência das linhagens celulares estudas. Assim, os dados obtidos nesse estudo podem ser considerados informações preliminares sobre o papel da enzima metiltransferase G9a na biologia de tumores sólidos pediátricos.Pediatric tumors are considered a rare type of cancer. Despite that, they are the second leading cause of death in pediatric patients. Medulloblastoma, neuroblastoma, and Ewing's sarcoma account for more than 30% of pediatric neoplasms. Epigenetic mechanisms are important for tumor development and progression. The present study seeks to explore the role of histone methyltransferase G9a in cellular processes relevant to the development of medulloblastoma, neuroblastoma and Ewing's sarcoma. The results obtained suggest that there is an association between G9a levels and the tumorgenicity of these tumors. In addition, inhibition of G9a activity and alteration of H3K9 methylation levels were found to be involved in cell viability, gene expression and survivability of the studied cell lines. These results can be considered preliminary data about the role of the enzyme methyltransferase G9a in the biology of pediatric solid tumors

EHMT2/G9a as an epigenetic target in pediatric and adult brain tumors

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors

Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma

A member of the Trk family of neurotrophin receptors, tropomyosin receptor kinase B (TrkB, encoded by the NTRK2 gene) is an increasingly important target in various cancer types, including glioblastoma (GBM). EGFR is among the most frequently altered oncogenes in GBM, and EGFR inhibition has been tested as an experimental therapy. Functional interactions between EGFR and TrkB have been demonstrated. In the present study, we investigated the role of TrkB and EGFR, and their interactions, in GBM. Analyses of NTRK2 and EGFR gene expression from The Cancer Genome Atlas (TCGA) datasets showed an increase in NTRK2 expression in the proneural subtype of GBM, and a strong correlation between NTRK2 and EGFR expression in glioma CpG island methylator phenotype (G-CIMP+) samples. We showed that when TrkB and EGFR inhibitors were combined, the inhibitory effect on A172 human GBM cells was more pronounced than when either inhibitor was given alone. When U87MG GBM cells were xenografted into the flank of nude mice, tumor growth was delayed by treatment with TrkB and EGFR inhibitors, given alone or combined, only at specific time points. Intracranial GBM growth in mice was not significantly affected by drug treatments. Our findings indicate that correlations between NTRK2 and EGFR expression occur in specific GBM subgroups. Also, our results using cultured cells suggest for the first time the potential of combining TrkB and EGFR inhibition for the treatment of GBM

Combined Inhibition of HDAC and EGFR Reduces Viability and Proliferation and Enhances STAT3 mRNA Expression in Glioblastoma Cells

Changes in expression of histone deacetylases (HDACs), which epigenetically regulate chromatin structure, and mutations and amplifications of the EGFR gene, which codes for the epidermal growth factor receptor (EGFR), have been reported in glioblastoma (GBM), the most common and malignant type of brain tumor. There are likely interplays between HDACs and EGFR in promoting GBM progression, and HDAC inhibition can cooperate with EGFR blockade in reducing the growth of lung cancer cells. Here, we found that either HDAC or EGFR inhibitors dose-dependently reduced the viability of U87 and A-172 human GBM cells. In U87 cells, the combined inhibition of HDACs and EGFR was more effective than inhibiting either target alone in reducing viability and long-term proliferation. In addition, HDAC or EGFR inhibition, alone or combined, led to G0/G1 cell cycle arrest. The EGFR inhibitor alone or combined with HDAC inhibition increased mRNA expression of the signal transducer and activator of transcription 3 (STAT3), which can act either as an oncogene or a tumor suppressor in GBM. These data provide early evidence that combining HDAC and EGFR inhibition may be an effective strategy to reduce GBM growth, through a mechanism possibly involving STAT3