<i>MYCN</i>
            -amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling

Dzieran, J; Garcia, Aida Rodriguez; Westermark, Ulrica; Henley, Aine Brigette; Sánchez, Eva; Träger, Catarina; Johansson, Henrik J.; Lehtiö, Janne; Arsenian-Henriksson, Marie

doi:10.1073/pnas.1710901115

Cited by 53 publications

(55 citation statements)

References 63 publications

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“…1d). It was reported that NGFR was downregulated by MYCN amplification to maintain an undifferentiated and more aggressive phenotype 20 . SNCG is traditionally characterized as a neuronal marker which is highly expressed in peripheral sensory neurons 21 .…”

Section: Hypoxia Represses Ra-induced Neuron Differentiation Markers mentioning

confidence: 99%

Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia

Gruber

Litzenburger

et al. 2020

Cell Death Dis

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Despite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why cancer cells waste most of the glucose carbon as lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation. Hypoxia is a common tumor microenvironmental stress that induces the Warburg effect and blocks tumor cell differentiation. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma differentiation model, we discovered that hypoxia repressed cell differentiation through reducing cellular acetyl-CoA levels, leading to reduction of global histone acetylation and chromatin accessibility. The metabolic switch triggering this global histone hypoacetylation was the induction of pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored acetyl-CoA generation and histone acetylation under hypoxia. Knocking down PDK1 induced neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly, acetate or glycerol triacetate (GTA) supplementation restored differentiation markers expression and neuron differentiation under hypoxia. Moreover, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduced chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. In addition, hypoxia-induced histone hypermethylation by increasing 2-hydroxyglutarate (2HG) and reducing α-ketoglutarate (αKG). αKG supplementation reduced histone hypermethylation upon hypoxia, but did not restore histone acetylation or differentiation markers expression. Together, these findings suggest that diverting pyruvate flux away from acetyl-CoA generation to lactate production is the key mechanism that Warburg effect drives dedifferentiation and tumorigenesis. We propose that combining differentiation therapy with acetate/GTA supplementation might represent an effective therapy against neuroblastoma.

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Section: Hypoxia Represses Ra-induced Neuron Differentiation Markers mentioning

confidence: 99%

Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia

Gruber

Litzenburger

et al. 2020

Cell Death Dis

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“…Current therapy for neuroblastoma, involves surgery, chemotherapy, monoclonal antibody treatment, and radiotherapy 38 with efficacy of each treatment depending on the disease stage and its biological features 39 . Surgery alone may achieve remission of MYCN-amplified neuroblastoma if it remains localized 38 but usually patients receive 13-cis-retinotic acid treatment to induce neuronal differentiation 40 and maintain a minimal residue disease 41 although patients frequently develop 13-cis-retinotic acid resistance leading to relapse 42 . Anti-GD2 antibody therapies combined with granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinotic acid have improved the 2-year survival rate by 20% 40,43,44 , but neuroblastoma cells with low GD2 expression fail to respond to this therapy 45 and so the prognosis of high-risk neuroblastoma remains very poor 43,46 and new treatments are required.…”

Section: Discussionmentioning

confidence: 99%

Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells

Meng¹,

Tagalakis

Hart

2020

Sci Rep

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Methods Ethics approval. All in vivo procedures were approved by UCL animal care policies and were carried out under Home Office Licenses issued in accordance with the United Kingdom Animals (Scientific Procedures) Act 1986 (UK). Materials. 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), 1,2-dipalmitoyl-sn-glycero-3-p hosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DPPE-PEG2000) and 1,2-dioleoyl-sn-glycero-3-p hosphoethanolamine (DOPE) were purchased from Avanti Polar Lipids, Inc. (Alabaster, AL, USA). Peptide ME27 (K16RVRRGACRGDCLG) was synthesized by Alta Bioscience (Birmingham, UK). Cell culture. Two p53-mutant neuroblastoma cell lines, Kelly 47,56 and SK-N-BE-2 (BE2) cells 5 were maintained in vitro in RPMI-1640 medium (Sigma, Dorset, UK) supplemented with 2 mM Glutamine and 10% FBS (Thermo Fisher, Paisley, UK). Cells were split every 3-4 days.

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“…Moreover, a large number of studies have demonstrated that the MYCN gene is closely related to neuroblastoma . A study by Zaatiti et al indicated that neuroblastoma IMR‐32 cell lines had significantly decreased proliferation ability after MYCN knockout .…”

Section: Discussionmentioning

confidence: 99%

MYCN gene polymorphisms and Wilms tumor susceptibility in Chinese children

Huang

Zhao

Zhu

et al. 2019

Clinical Laboratory Analysis

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Background Wilms tumor, derived from embryonic cells, accounts for a large proportion of pediatric renal tumors. MYCN encoded by MYCN proto‐oncogene, a member of the MYC family, is a BHLH transcription factor. It plays a critical role in tumorigenesis and predicts poor clinical outcomes in various types of cancer. However, the role of MYCN remained unclarified in Wilms tumor. In this study, we investigated the association between MYCN gene polymorphisms and Wilms tumor susceptibility. Methods Four MYCN gene polymorphisms (rs57961569 G > A, rs9653226 T > C, rs13034994 A > G, and rs60226897 G > A) were genotyped in 183 cases and 603 controls. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated to evaluate the association between MYCN gene polymorphisms and Wilms tumor susceptibility. Results Overall, no significant association was found for any of the four MYCN gene polymorphisms. Interestingly, in the stratification analysis, the rs57961569 was found to be associated with decreased Wilms tumor susceptibility in the children older than 18 months (AOR = 0.65, 95% CI = 0.42‐1.00, P = .050). Moreover, older children carrying 2‐4 risk genotypes were at increased risk of Wilms tumor (OR = 1.55, 95% CI = 1.001‐2.40, P = .0497). Haplotype GCAA was shown to significantly increased Wilms tumor risk (AOR = 2.40, 95% CI = 1.12‐5.14, P = .024). Conclusion Our study demonstrated that these MYCN gene polymorphisms might be low penetrant variants in Wilms tumor.

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MYCN -amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling

Cited by 53 publications

References 63 publications

Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia

Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia

Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells

MYCN gene polymorphisms and Wilms tumor susceptibility in Chinese children

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