RESUMO
Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the histone deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant functions and common substrates, the unique isoform-specific roles of different HDACs in GBM remain unclear. In neural stem cells, HDAC2 is the indispensable deacetylase to ensure normal brain development and survival in the absence of HDAC1. Surprisingly, we find that HDAC1 is the essential class I deacetylase in glioma stem cells, and its loss is not compensated for by HDAC2. Using cell-based and biochemical assays, transcriptomic analyses, and patient-derived xenograft models, we find that knockdown of HDAC1 alone has profound effects on the glioma stem cell phenotype in a p53-dependent manner. We demonstrate marked suppression in tumor growth upon targeting of HDAC1 and identify compensatory pathways that provide insights into combination therapies for GBM. Our study highlights the importance of HDAC1 in GBM and the need to develop isoform-specific drugs.
Assuntos
DNA de Neoplasias/genética , Glioma/genética , Histona Desacetilase 1/genética , Mutação , Células-Tronco Neoplásicas/metabolismo , Apoptose , Perfilação da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Histona Desacetilase 1/metabolismo , Humanos , Isoformas de Proteínas/genética , Células Tumorais CultivadasRESUMO
Microbial production of fuels and chemicals from lignocellulosic biomass provides a promising alternative to conventional petroleum-derived routes. However, the heterogeneous sugar composition of lignocellulose prevents efficient microbial sugar co-fermentation due to carbon catabolite repression, which negatively affects production metrics. We previously discovered that a mutant copy of the transcriptional regulator XylR (P363S and R121C; denoted as XylR*) in Escherichia coli has a higher DNA-binding affinity than wild-type XylR, leading to a stronger activation of the d-xylose catabolic genes and a release from glucose-induced repression on xylose fermentation. Here, we showed that XylR* also releases l-arabinose-induced repression on xylose fermentation through altered transcriptional control, enhancing co-fermentation of arabinose-xylose sugar mixtures in wild-type E. coli. Integrating xylR* into an ethanologenic E. coli resulted in the coutilization of 96% of the provided glucose-xylose-arabinose mixtures (120 g/L total sugars supplied) with an ethanol yield higher than 90% of the theoretical maximum by simple batch fermentations.