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Super-enhancer-associated oncogenes as novel therapeutic targets in osteosarcoma (ChIP-seq)

ABSTRACT: Despite the development of diagnostic and advanced treatment strategies, the prognosis of patients with osteosarcoma remains poor. A limited understanding of the pathogenesis of osteosarcomas has impeded any improvement in patient outcomes over the past 4 decades. It is thus urgent to identify novel effective targets and treatment regimens for osteosarcoma patients. In this study we delineated the super-enhancer landscape in osteosarcoma cells on the basis of H3K27ac signal intensity by ChIP-Seq and found that super-enhancer-associated genes contribute to the malignant potential of osteosarcoma. THZ2, a novel small molecular inhibitor, shows a powerful anti-osteosarcoma ability through suppress super-enhancer-associated genes selectively. Utilizing the characteristics of super-enhancers in cancer cells, we identified 5 critical super-enhancer-associated oncogenes. With the comparative and retrospective analysis in large numbers of human specimens from patients, these 5 oncogenes were observed closely related with patient prognosis. Our findings determined that targeting super-enhancer-associated oncogenes with transcriptional inhibitor, THZ2, was a promising therapeutic strategy in osteosarcoma, and provided novel candidate targets for patients with osteosarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134604 | GEO | 2019/12/27

REPOSITORIES: GEO

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Project description:Osteosarcoma is the most common malignancy of bone, and occurs most frequently in children and adolescents. Currently, the most reliable technique for prognostication is measuring histopathologic tumor necrosis following preoperative chemotherapy, and favourable prognosis is signified by 90% or greater estimated necrosis of the tumour. Neither genetic testing nor molecular biomarkers have been described for this tumour. We used the novel nanoString mRNA expression analysis system to analyzed total RNA from 35 flash-frozen sporadic paediatric osteosarcoma biopsy and resection specimens to quantify mRNA expression for 17 oncogenes and tumour suppressor genes. Three oncogenes, cell cycle regulator gene CDC5L, the RecQ DNA helicase gene RECQL4, and the cyclin-dependent kinase gene CDK4, were more highly expressed (p<0.05) in tumours which responded poorly to neoadjuvant chemotherapy. A similar trend (p<0.10) was identified for the osteoblast-specific transcription factor gene RUNX2. No statistically significant difference existed in comparing expression of CDC5L, RECQL4, CDK4, and RUNX2 between biopsy and resection samples. Additionally, analysis of expression data in the context of histological subtype yielded preliminary results for deducing molecular subtypes of osteosarcomas. Osteoblastic osteosarcomas possessed higher expression of CDKN1A, PTEN, and RUNX2 relative to their fibroblastic counterparts (p<0.05). This research study shows that CDC5L, RECQL4, and CDK4 tumour expression levels may be useful for identifying patients who may not benefit from the current standardized chemotherapy regimen. Total RNA was isolated from 52 pediatric osteosarcoma samples (prechemotherapy biopsies and resections), 3 osteosarcoma cell lines, and normal human osteoblasts. nanoString mRNA expression analysis was applied to samples split between 3 batches to compare samples based on clinical and pathologic data reports, and to compare samples with normal human osteoblasts. For 43 samples, there were complete data and the RNA was successfully assayed. Analysis was performed using R.

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Super-enhancer-associated oncogenes as novel therapeutic targets in osteosarcoma (ChIP-seq)

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