RESUMEN
Glioblastoma (GBM) is the most common, malignant, and aggressive form of glial cell cancer with unfavorable clinical outcomes. It is believed that a better understanding of the mechanisms of gene deregulation may lead to novel therapeutic approaches for this yet incurable cancer. Mediator complex is a crucial component of enhancer-based gene expression and works as a transcriptional co-activator. Many of the mediator complex subunits are found to be deregulated/mutated in various malignancies; however, their status and role in GBM remains little studied. We report that MED30, a core subunit of the head module, is overexpressed in GBM tissues and cell lines. MED30 was found to be induced by conditions present in the tumor microenvironment such as hypoxia, serum, and glucose deprivation. MED30 harbors hypoxia response elements (HREs) and p53 binding site in its promoter and is induced in a HIF1α and p53 dependent manner. Further, MED30 levels also significantly positively correlated with p53 and HIF1α levels in GBM tissues. Using both MED30 overexpression and knockdown approach, we show that MED30 promotes cell proliferation while reduces the migration capabilities in GBM cell lines. Notably, MED30 was also found to confer sensitivity to chemodrug, temozolomide, in GBM cells and modulate the level of p53 in vitro. Overall, this is the first report showing MED30 overexpression in GBM and its involvement in GBM pathogenesis suggesting its diagnostic and therapeutic potential urging the need for further systematic exploration of MED30 interactome and target networks.
Asunto(s)
Glioblastoma/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Complejo Mediador/metabolismo , Temozolomida/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Complejo Mediador/genética , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Synthetic DNA-binding inhibitors capable of gaining precise control over neurogenesis factors could obviate the current clinical barriers associated with the use of small molecules in regenerative medicine. Here, we report the design and bioefficacy of the synthetic ligand PIP-RBPJ-1, which caused promoter-specific suppression of neurogenesis-associated HES1 and its downstream genes. Furthermore, PIP-RBPJ-1 alone altered the neural-system-associated Notch-signaling factors and remarkably induced neurogenesis with an efficiency that was comparable to that of a conventional approach.