Aryl Hydrocarbon Receptor Downregulates MYCN Expression and Promotes Cell Differentiation of Neuroblastoma

Wu, Pei-Shan; Liao, Yung-Feng; Juan, Hsueh‐Fen; Huang, Hsuan‐Cheng; Wang, Bo-Jeng; Lu, Yi Chia; Yu, I‐Shing; Shih, Yu-Yin; Jeng, Yung‐Ming; Hsu, Wen-Ming; Lee, Hsinyu

doi:10.1371/journal.pone.0088795

Cited by 28 publications

(32 citation statements)

References 44 publications

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“…Forced expression of MYCN can transform normal cells in vitro (5) and is sufficient to drive neuroblastoma tumorigenesis in model animals, such as zebrafish (6) and mice (7). Recently, MYCN and aryl hydrocarbon receptor (AHR) expression levels were found to be inversely correlated in neuroblastoma, and AHR overexpression downregulated MYCN, promoting neuroblastoma cell differentiation (8).…”

Section: Introductionmentioning

confidence: 99%

Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma

Lin

et al. 2019

Cancer Research

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Neuroblastoma is the most common malignant disease of infancy, and amplification of the MYCN oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. kynurenine treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of KISS1 levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that KISS1 expression positively correlated with AHR, and high KISS1 expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. Significance: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.

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Section: Introductionmentioning

confidence: 99%

Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma

Lin

et al. 2019

Cancer Research

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“…seen with the XRE-luc vector. As ODC1 is also a well-established target of MYC (8,9) and MYC itself has been shown to potentially be a target of AHR (50)(51)(52)(53)(54), we extended the sequence of ODC1p in the above construct to include MYC binding elements, either WT or mutated, to abrogate binding. We performed luciferase reporter assays as described above.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

Bianchi‐Smiraglia¹,

Bagati²,

Fink³

et al. 2018

Journal of Clinical Investigation

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Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

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“…The difference between the mRNA and protein expression of NSE observed in ATRA‐treated condition was observed in other studies as well. The differentiation of SK‐N‐DZ cells by overexpression of the aryl hydrocarbon receptor showed no change in the regulation of NSE at transcript levels . These data suggest that the transcripts of neuronal markers might be regulated via post‐transcriptional regulatory mechanisms.…”

Section: Discussionmentioning

confidence: 82%

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

et al. 2019

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Neuroblastoma is an embryonic malignancy that arises out of the neural crest cells of the sympathetic nervous system. It is the most common childhood tumor known for its spontaneous regression via the process of differentiation. The induction of differentiation using small molecules such as retinoic acid is one of the therapeutic strategies to treat the residual disease. In this study, we have reported the effect of kaempferol (KFL) in inducing differentiation of neuroblastoma cells in vitro. Treatment of neuroblastoma cells with KFL reduced the proliferation and enhanced apoptosis along with the induction of neuritogenesis. Analysis of the expression of neuron‐specific markers such as β‐III tubulin, neuron‐specific enolase, and N‐myc downregulated gene 1 revealed the process of differentiation accompanying KFL‐induced apoptosis. Further analysis to understand the molecular mechanism of action showed that the effect of KFL is mediated by the activation of the endoribonuclease activity of inositol‐requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum‐resident transmembrane protein. In silico docking analysis and biochemical assays using recombinant human IRE1α confirm the binding of KFL to the ATP‐binding site of IRE1α, which thereby activates IRE1α ribonuclease activity. Treatment of cells with the small molecule STF083010, which specifically targets and inhibits the endoribonuclease activity of IRE1α, showed reduced expression of neuron‐specific markers and curtailed neuritogenesis. The knockdown of IRE1α using plasmid‐based shRNA lentiviral particles also showed diminished changes in the morphology of the cells upon KFL treatment. Thus, our study suggests that KFL induces differentiation of neuroblastoma cells via the IRE1α ‐XBP1 pathway.

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Aryl Hydrocarbon Receptor Downregulates MYCN Expression and Promotes Cell Differentiation of Neuroblastoma

Cited by 28 publications

References 44 publications

Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma

Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

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