MYCN-enhanced Oxidative and Glycolytic Metabolism Reveals Vulnerabilities for Targeting Neuroblastoma

Oliynyk, Ganna; Ruiz-Pérez, María Victoria; Sainero-Alcolado, Lourdes; Dzieran, J; Zirath, Hanna; Gallart-Ayala, Héctor; Wheelock, Craig E.; Johansson, Henrik J.; Nilsson, Roland; Lehtiö, Janne; Arsenian-Henriksson, Marie

doi:10.1016/j.isci.2019.10.020

Cited by 58 publications

(70 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we identify HNF4A as a transcription factor facilitating expression of glycolytic genes HK2 and SLC2A1 in NB. Recent studies indicate that as an oncogene associated with poor survival, MYCN is essential for aerobic glycolysis in NB [31], while the underlying mechanisms remain elusive. We demonstrate that as a MYCN-facilitated lncRNA, HNF4A-AS1 interacts with hnRNPU protein to facilitate transactivation of CTCF, which epigenetically regulates transcription of HNF4A and other genes associated with tumor progression in cis and in trans (Fig.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: HNF4A-AS1/hnRNPU/CTCF axis as a therapeutic target for aerobic glycolysis and neuroblastoma progression

Song

Wang

et al. 2020

J Hematol Oncol

View full text Add to dashboard Cite

Background: Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to tumor progression. However, the mechanisms regulating expression of glycolytic genes in neuroblastoma (NB), the most common extracranial solid tumor in childhood, still remain elusive. Methods: Crucial transcriptional regulators and their downstream glycolytic genes were identified by integrative analysis of a publicly available expression profiling dataset. In vitro and in vivo assays were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. Survival analysis was performed by using Kaplan-Meier method and log-rank test. Results: Hepatocyte nuclear factor 4 alpha (HNF4A) and its derived long noncoding RNA (HNF4A-AS1) promoted aerobic glycolysis and NB progression. Gain-and loss-of-function studies indicated that HNF4A and HNF4A-AS1 facilitated the glycolysis process, glucose uptake, lactate production, and ATP levels of NB cells. Mechanistically, transcription factor HNF4A increased the expression of hexokinase 2 (HK2) and solute carrier family 2 member 1 (SLC2A1), while HNF4A-AS1 bound to heterogeneous nuclear ribonucleoprotein U (hnRNPU) to facilitate its interaction with CCCTC-binding factor (CTCF), resulting in transactivation of CTCF and transcriptional alteration of HNF4A and other genes associated with tumor progression. Administration of a small peptide blocking HNF4A-AS1-hnRNPU interaction or lentivirus-mediated short hairpin RNA targeting HNF4A-AS1 significantly suppressed aerobic glycolysis, tumorigenesis, and aggressiveness of NB cells. In clinical NB cases, high expression of HNF4A-AS1, hnRNPU, CTCF, or HNF4A was associated with poor survival of patients. Conclusions: These findings suggest that therapeutic targeting of HNF4A-AS1/hnRNPU/CTCF axis inhibits aerobic glycolysis and NB progression.

show abstract

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: HNF4A-AS1/hnRNPU/CTCF axis as a therapeutic target for aerobic glycolysis and neuroblastoma progression

Song

Wang

et al. 2020

J Hematol Oncol

View full text Add to dashboard Cite

show abstract

“…MYCN-amplified neuroblastoma cells exhibit enhanced expression of genes and proteins involved in aerobic glycolysis (Warburg effect), oxidative phosphorylation (OXPHOS), detoxification of reactive oxygen species (ROS), and FAO (45). In MYCN-amplified tumor cells, glycolytic enzymes including hexokinase isoform 2 are upregulated, and enzymes associated with the TCA cycle and the electron transport chain, such as citrate synthase and isocitrate dehydrogenase isoform 2, are expressed at high levels.…”

Section: Mitochondrial Metabolic Reprogramming In N-myc-driven Cancermentioning

confidence: 99%

“…In MYCN-amplified tumor cells, glycolytic enzymes including hexokinase isoform 2 are upregulated, and enzymes associated with the TCA cycle and the electron transport chain, such as citrate synthase and isocitrate dehydrogenase isoform 2, are expressed at high levels. Increased expression of N-Myc-induced respiratory subunit genes is correlated with adverse clinical outcome in patients with neuroblastoma (45). A moderate increase in ROS in malignant neoplasms modulates cancer cellular signaling via the oxidation of cysteine.…”

Section: Mitochondrial Metabolic Reprogramming In N-myc-driven Cancermentioning

confidence: 99%

Beyond the Warburg Effect: N-Myc Contributes to Metabolic Reprogramming in Cancer Cells

Yoshida

2020

Front. Oncol.

View full text Add to dashboard Cite

Cancer cells generate large amounts of lactate derived from glucose regardless of the available oxygen level. Cancer cells finely control ATP synthesis by modulating the uptake of substrates and the activity of enzymes involved in aerobic glycolysis (Warburg effect), which enables them to adapt to the tumor microenvironment. However, increasing evidence suggests that mitochondrial metabolism, including the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and glutaminolysis, is paradoxically activated in MYCN-amplified malignancies. Unlike non-amplified cells, MYCN-amplified cancer cells significantly promote OXPHOS-dependent ATP synthesis. Furthermore, tumor cells are differentially dependent on fatty acid β-oxidation (FAO) according to N-Myc status. Therefore, upregulation of FAO-associated enzymes is positively correlated with both N-Myc expression level and poor clinical outcome. This review explores therapeutic strategies targeting cancer stem-like cells for the treatment of tumors associated with MYCN amplification.

show abstract

“…While this paper was in review, this was confirmed by results from Oliynyk et al who showed that N-Myc increases the glycolytic and oxidative phosphorylation capacity of MYCN-amplified neuroblastoma cells. Moreover, they could demonstrate glutamine independence of mitochondrial respiration in MYCN-amplified neuroblastoma cells compared with non-MYCN amplified cells and that N-Myc high cells are especially vulnerable to inhibition of fatty acid oxidation 34 . We can conclude from these results that N-Myc reprograms neuroblastoma cells towards a highly energy producing and consuming phenotype.…”

Section: Discussionmentioning

confidence: 99%

N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

Tjaden

Baum

Marquardt

et al. 2020

Sci Rep

View full text Add to dashboard Cite

n-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of n-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.Myc proteins are encoded by a small family of proto-oncogenes consisting of MYC, MYCN and MYCL. In normal tissues, their expression is tightly regulated, while deregulation of MYC family members has been identified as a driving force in different cancer types. Since specific binding motifs, termed E-boxes, had been identified early on, Myc proteins were considered to be gene-specific transcription factors. This concept has been recently extended by different studies suggesting that deregulated Myc in tumors functions as a general transcriptional amplifier 1-3 . However, Myc-induced and tumor-specific mechanisms of target gene control on transcriptional level have only recently been addressed mechanistically 4 . The picture emerges that, at least in settings with vastly elevated Myc-levels, enhancer invasion by N-Myc and associated proteins contributes to tumor-specific N-Myc signatures. Moreover, the concept of Myc-mediated cell autonomous effects to boost tumor cell proliferation has been extended to include restriction of host immune reactions towards a tumor 5 . Although these efforts led to

show abstract

MYCN-enhanced Oxidative and Glycolytic Metabolism Reveals Vulnerabilities for Targeting Neuroblastoma

Cited by 58 publications

References 48 publications

RETRACTED ARTICLE: HNF4A-AS1/hnRNPU/CTCF axis as a therapeutic target for aerobic glycolysis and neuroblastoma progression

RETRACTED ARTICLE: HNF4A-AS1/hnRNPU/CTCF axis as a therapeutic target for aerobic glycolysis and neuroblastoma progression

Beyond the Warburg Effect: N-Myc Contributes to Metabolic Reprogramming in Cancer Cells

N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

Contact Info

Product

Resources

About