BCL6 enforces human glioblastoma growth and serves as a novel therapeutic target (expression)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE77053 | GEO | 2016/08/01
SECONDARY ACCESSION(S): PRJNA309336
REPOSITORIES: GEO
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Project description:ZBTB transcription factors extensively orchestrate gene transcription during tissue development. However, their roles in glioblastoma multiforme (GBM) remain largely unexplored. Here, through integrated functional screening and expression analyses of 49 human ZBTB genes, we identify that BCL6 is required for GBM cell proliferation and is overexpressed in GBM samples. High expression of BCL6 is associated with poor overall survival of GBM patients. Genome-wide occupancy analysis and transcriptome analysis demonstrates that BCL6 is recruited to the loci of various tumor-promoting genes (e.g. MYC, FOSL1, MALAT1 and NEAT1) and maintains their expression. Pathway enrichment analysis reveals that BCL6 regulates several important cancer related pathways (e.g. TP53, ErbB and MAPK signaling pathways). BCL6 represses the expression of TP53 and its target genes, CDKN1A and CDKN1B, thereby promoting GBM cell resistance to ionizing radiation. Moreover, antibody array profiling uncovers AXL and MET are selectively activated by BCL6 in GBM. Moreover, BCL6 enhances both MEKERK and S6K-RPS6 axes as well as cap-dependent translation through the induction of AXL expression. Importantly, depletion of BCL6 or pharmacological inhibition of BCL6/NCoR complex effectively blocks GBM growth both in vitro and in vivo, and sensitizes GBM cells to EGFR inhibitors. Together, these findings uncover a novel growth-promoting role of BCL6 in GBM, and provide the rationale of targeting BCL6 as a potential therapeutic approach for this deadly malignancy. cDNA microarray analysis was performed in U87 cells transfected with either non-targeting siRNAs or BCL6 siRNAs. All experiments were carried out in duplicates.
2016-08-01 | E-GEOD-77053 | biostudies-arrayexpress
Project description:For MS of BCL6 modification sites and interaction proteins, the gel band of BCL6 was excised and digested with trypsin. Immunocomplexes were identified on Thermo Scientific Orbitrap Fusion Lumos. The data for this project include raw data.
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Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286179 | GEO
Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286319 | GEO
Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286318 | GEO
Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286432 | GEO
Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286320 | GEO
Project description:Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands.
2016-10-12 | GSE80351 | GEO
Project description:Most small-molecule protein degraders act as interface stabilizers ‘molecular glues’ between E3 ubiquitin ligases and target proteins to induce ternary complex formation and ubiquitin-dependent target protein degradation. Here we report polymerization as a novel mechanism for small molecule-induced degradation. Using functional screens in combination with molecular and biochemical assays, we found that BI-3802, which binds to the BTB domain of the oncogenic transcription factor BCL6, induces polymerization of BCL6 into regular helical structures in vitro and foci in vivo. Polymerization precedes degradation by the SIAH1 E3 ubiquitin ligase. Hereby, a VxP amino acid motif on BCL6, distal from the drug-binding BTB domain, is required for SIAH1 binding, ubiquitination and BI-3802-induced degradation. Our findings propose that small molecule-induced polymerization is not only a new modality for targeted protein degradation, but also provides synthetic biology with a tool for tunable protein polymerization and opens new avenues for future drug design.
2020-11-20 | PXD016185 | Pride
Project description:Rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) for BCL6 in untreated and irradiated glioblastoma cell lines and a positive control lymphoma cell line.
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