Glioblastoma (GBM) is the most aggressive tumor of the central nervous system, and the identification of the mechanisms underlying the biological basis of GBM aggressiveness is essential to develop new therapies. Due to the low prognosis of GBM treatment, different clinical studies are in course to test the use of histone deacetylase inhibitors (iHDACs) in anticancer cocktails. Here, we seek to investigate the impact of HDAC activity on GBM cell behavior and plasticity by live cell imaging. We pharmacologically knock down HDAC activity using two different inhibitors (TSA and SAHA) in two different tumor cell types: a commercial GBM cell line (U87-MG) and primary tumor (GBM011). Upon 72 hours of in vitro iHDAC treatment, GBM cells presented a very unusual elongated cell shape due to tunneling tube formation and independent on TGF-β signaling epithelial to mesenchymal transition. Live cell imaging revealed that voltage-sensitive Ca++ signaling was disrupted upon HDAC activity blockade. This behavior was coupled to vimentin and connexin 43 gene expression downregulation, suggesting that HDAC activity blockade downgrades GBM aggressiveness mostly due to tumor cell competence and plasticity modulation in vitro. To test this hypothesis and access whether iHDACs would modulate tumor cell behavior and plasticity to properly respond to environmental cues in vivo, we xenografted GBM oncospheres in the chick developing the neural tube. Remarkably, upon 5 days in the developing neural tube, iHDAC-treated GBM cells ectopically expressed HNK-1, a tumor-suppressor marker tightly correlated to increased survivor of patients. These results describe, for the first time in the literature, the relevance of iHDACs for in vivo tumor cell morphology and competence to properly respond to environmental cues. Ultimately, our results highlight the relevance of chromatin remodeling for tumor cell plasticity and shed light on clinical perspectives aiming the epigenome as a relevant therapeutic target for GBM therapy.
ResumoIntrodução: a obesidade, uma pandemia mundial, é uma condição clínica que se relaciona com diversas comorbidades, como a hipertensão arterial, que pode ser farmacologicamente tratada com Losartan. A complexidade da obesidade associada ao uso de medicamentos poderia programar metabolicamente diversos sistemas orgânicos, como o tecido ósseo. Objetivo: verificar os potenciais efeitos da obesidade associada ao uso de Losartan como programador metabólico sobre parâmetros histomorfométricos do tecido ósseo da prole. Metodologia: Foram utilizadas ratas Wistar, divididas em grupos controle (CTL), que recebeu ração padrão e água; e tratado (CAF+ LOS), que recebeu dieta de cafeteria ad libitum e Losartan diariamente por meio de gavagem. Aos 70 dias de vida as ratas foram submetidas ao cruzamento com machos da mesma espécie. A partir dos 21 dias de vida, a prole foi alimentada com ração padrão até os 100 dias de vida, quando 8 fêmeas de cada grupo foram pesadas e eutanasiadas. Foram coletadas e pesadas as gorduras retroperitoneal e perigonadal. Em seguida, as tíbias direitas foram coletadas e submetidas ao processamento histológico de rotina para microscopia de luz, com posterior análise de parâmetros histomorfométricos. Resultados: houve um aumento estatisticamente significativo no acúmulo de gordura perigonadal nas ratas do grupo CAF+LOS, bem como menor área do canal medular da tíbia nestas ratas em relação ao grupo CTL. Conclusão: a obesidade induzida por dieta de cafeteria associada ao uso de Losartan programou a prole por meio do aumento no acúmulo de gordura perigonadal e redução da área do canal medular da tíbia. Palavras-chave: Tecido Adiposo. Hipertensão. Tíbia. Abstract Introduction: obesity, a global pandemic, is a clinical condition that is associated with several co-morbidities such as hypertension
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