ArticleProceedings of the National Academy of Sciences of the United States of America2017
Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 59 citations in OpenAlex.
- HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Comprehensive analysis of disulfidoptosis-related genes reveals molecular heterogeneity and key regulators in retinoblastoma progression.Translational pediatrics · 2025Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- The Hypoxia-Retinoid Axis in Idiopathic Pulmonary Fibrosis: Multifaceted Etiology and Therapeutic Potential.International journal of molecular sciences · 2025Review
- Mitochondrial uncoupler and retinoic acid synergistically induce differentiation and inhibit proliferation in neuroblastoma.bioRxiv : the preprint server for biology · 2024Article
- Induction ofJournal of clinical biochemistry and nutrition · 2023Article
- Identification of a novel gene signature for neuroblastoma differentiation using a Boolean implication network.Genes, chromosomes & cancer · 2023Article
- AKT inhibitor Hu7691 induces differentiation of neuroblastoma cells.Acta pharmaceutica Sinica. B · 2023Article
- Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma.Cancer research · 2023Article
- HIF and MYC signaling in adrenal neoplasms of the neural crest: implications for pediatrics.Frontiers in endocrinology · 2023Review
- EPAS1/HIF-2α Acts as an Unanticipated Tumor-Suppressive Role in Papillary Thyroid Carcinoma.International journal of general medicine · 2023Article
- MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment.Cancers · 2022Review
- Crosstalk among mJournal of hematology & oncology · 2022Review
- Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy.Cancers · 2022Review
- Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells.Frontiers in cell and developmental biology · 2022Article
- Engaging plasticity: Differentiation therapy in solid tumors.Frontiers in pharmacology · 2022Review
- Combination of a synthetic retinoid and a DNA demethylating agent induced differentiation of neuroblastoma through retinoic acid signal reprogramming.British journal of cancer · 2021Article
- MYCN in Neuroblastoma: "Old Wine into New Wineskins".Diseases (Basel, Switzerland) · 2021Review
- Article
- Adoptive transfer of immature myeloid cells lacking NF-κB p50 (p50-IMC) impedes the growth of MHC-matched high-risk neuroblastoma.Molecular oncology · 2021Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as
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