Super-enhancer-associated TTC8 promotes neuroblastoma progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE188562 | GEO | 2022/08/29
REPOSITORIES: GEO
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Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
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Project description:Bromodomain-containing protein 4 (BRD4) functions as an epigenetic reader and binds to so-called super-enhancer regions of driving oncogenes such as MYC in cancer. We investigated the possibility to target super-enhancer regulated genes in neuroblastoma and in MYCN amplified disease in particular. We used OTX015, the first small-molecule BRD4 inhibitor to enter clinical phase I/II trials in adults, to test the feasibility to specifically target super-enhancer regulated gene-expression in neuroblastoma. BRD4 inhibition lead to significant transcriptional down-regulation of genes that were associated with super-enhancers, supporting the notion that BRD4 preferentially acts at these chromatin sites. BRD4 inhibition not only attenuated MYCN transcription but most significantly affected MYCN-regulated transcriptional programs.
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Project description:Intra-tumour heterogeneity is increasingly appreciated as a determinant of tumour recurrence. Several tumour types were recently found to include phenotypically divergent cell types, reflecting lineage development stages (1,2,3). Lineage identity has been proposed to ensue super-enhancer (SE)-associated transcription factor (TF) networks (4,5), but their role in intra-tumour heterogeneity is unknown. Neuroblastoma is a paediatric tumour of the adrenergic differentiation lineage. Here we show that most neuroblastoma tumors include two types of tumor cells with highly diverging gene expression profiles. The undifferentiated mesenchymal cells and more differentiated adrenergic cells can interconvert and may relate to normal lineage differentiation stages. ChIP-seq analysis of isogenic pairs of mesenchymal and adrenergic neuroblastoma cells revealed a distinct, highly consistent super-enhancer landscape for each cell type. Two SE-associated TF networks emerged that potentially master each cell type. Accordingly, the mesenchymal TF PRRX1 could reprogram the SE- and mRNA-profiles of adrenergic cells towards a mesenchymal state. To assess the clinical relevance of this bi-phasic system, we investigated chemo-sensitivity of both cell types. Mesenchymal cells were more resistant in vitro and were enriched in post-therapy and relapsed neuroblastoma in patients. Intra-tumor heterogeneity in neuroblastoma is therefore structured according to distinct SE-associated transcriptional programs that mediate a dynamic bi-phasic structure.
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Project description:Neuroblastoma is a pediatric tumor that accounts for more than 15% of cancer-related deaths in children. Survival chances for high-risk patients are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumors respond to retinoic acid-mediated differentiation. Among neuroblastoma tumors, two phenotypically distinct cell types-adrenergic (ADRN) and mesenchymal (MES), have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries. We hypothesized that distinct super-enhancers in these different tumor cells could mediate differential response to retinoic acid. To this end, we treated four different neuroblastoma cell lines, comprising both ADRN (MYCN amplified and non-amplified) and MES subtypes, with retinoic acid and studied the super-enhancer landscape upon treatment and after removal of retinoic acid. Using H3K27ac ChIP-seq paired with RNA-seq, we compared the super-enhancers in cells that respond to retinoic acid-mediated differentiation versus those that fail to differentiate. We identified unique super-enhancers associated with cells differentiation; however, even among cells that respond to treatment, there was heterogeneity upon removal of retinoic acid, with MYCN amplified cells remaining differentiated whereas MYCN non-amplified cells reverted to a proliferative state. This study identifies regulatory super-enhancers as a plausible mechanism behind the differential response to retinoic acid-mediated differentiation.
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Project description:Neuroblastoma is a solid pediatric tumor with heterogeneous clinical behaviors. Chemotherapy is widely used to treat neuroblastoma. However, dose-dependent responses and chemoresistance mechanisms of neuroblastoma cells to anticancer drugs remain challenges in various conditions. Here, we investigated the dose-dependent effects of topotecan on human neuroblastoma cells (SK-N-SH, SH-SY5Y, and SK-N-BE) under various nutrient supply conditions. Serum-starved human neuroblastoma cells showed reduced toxicity, and their survival rate increased upon treatment with a high concentration (1 μM) of topotecan. Quantitative profiling of global and phosphoproteome identified 12,959 proteins and 48,812 phosphosites, respectively, from SK-N-SH cells. Network analysis revealed that topotecan up-regulated DNA repair and cholesterol-mediated topotecan efflux, resulting in topotecan resistance. Results of DNA damage assay, cell cycle, and quantitative analyses of membrane cholesterol supported the validity of these resistance factors and their applicability to all neuroblastoma cells investigated in this study. Our results provide a model for high dose-dependent chemoresistance in neuroblastoma cells that could enable a patient-dependent chemotherapy screening strategy.
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