{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":51,"searchCount":0},"additional":{"submitter":["Jin X"],"funding":["NINDS NIH HHS","NCI NIH HHS","NIGMS NIH HHS"],"pagination":["1352-1361"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5679732"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["23(11)"],"pubmed_abstract":["Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity."],"journal":["Nature medicine"],"pubmed_title":["Targeting glioma stem cells through combined BMI1 and EZH2 inhibition."],"pmcid":["PMC5679732"],"funding_grant_id":["R01 CA154130","R01 NS087913","F30 CA217065","R01 NS103434","R35 CA197718","F30 CA203101","T32 GM007250","R01 NS089272","R01 CA184090","R01 CA169117","R01 CA171652","R01 NS091080","R01 NS099175"],"pubmed_authors":["Jin X","Kim LJY","Wu Q","Rich JN","Prager BC","Sanvoranart T","Miller TE","Barnholtz-Sloan JS","Bao S","Valentim CL","Gimple RC","Huang P","Sloan AE","Wallace LC","Zhou QG","Wang X","Mack SC"],"view_count":["51"],"additional_accession":[]},"is_claimable":false,"name":"Targeting glioma stem cells through combined BMI1 and EZH2 inhibition.","description":"Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 Nov","modification":"2024-12-04T05:10:20.469Z","creation":"2019-03-26T23:25:51Z"},"accession":"S-EPMC5679732","cross_references":{"pubmed":["29035367"],"doi":["10.1038/nm.4415"]}}