Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma
Ian C. MacArthur, … , Alex Kentsis, Anton G. Henssen
Ian C. MacArthur, … , Alex Kentsis, Anton G. Henssen
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(10):e127130. https://doi.org/10.1172/jci.insight.127130.
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Research Article Genetics Oncology

Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma

Abstract

Gain of the long arm of chromosome 17 (17q) is a cytogenetic hallmark of high-risk neuroblastoma, yet its contribution to neuroblastoma pathogenesis remains incompletely understood. Combining whole-genome and RNA sequencing of neuroblastomas, we identified the prohibitin (PHB) gene as highly expressed in tumors with 17q gain. High PHB expression correlated with poor prognosis and was associated with loss of gene expression programs promoting neuronal development and differentiation. PHB depletion induced differentiation and apoptosis and slowed cell cycle progression of neuroblastoma cells, at least in part through impaired ERK1/2 activation. Conversely, ectopic expression of PHB was sufficient to increase proliferation of neuroblastoma cells and was associated with suppression of markers associated with neuronal differentiation and favorable neuroblastoma outcome. Thus, PHB is a 17q oncogene in neuroblastoma that promotes tumor cell proliferation and dedifferentiation.

Authors

Ian C. MacArthur, Yi Bei, Heathcliff Dorado Garcia, Michael V. Ortiz, Joern Toedling, Filippos Klironomos, Jana Rolff, Angelika Eggert, Johannes H. Schulte, Alex Kentsis, Anton G. Henssen

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Figure 1

Chromosome 17q gain in neuroblastoma is associated with high PHB copy number and expression and correlates with adverse patient prognosis.

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Chromosome 17q gain in neuroblastoma is associated with high PHB copy nu...
(A) Plot of chromosome 17 with regions of copy number gain (shown in blue) as detected in 56 patient samples of tumor-normal paired whole-genome sequencing. PHB locus indicated (black arrowhead). (B) Kaplan-Meier curve displaying overall survival for patients with low versus high PHB mRNA expression measured using RNA-Seq. P value calculated by log-rank test. (C) PHB expression in patients with 17q versus whole 17 or no gain. **P < 0.05, 2-tailed t test. (D) Heatmap of the significantly differentially expressed genes in patients with high versus low PHB expression. Statistical significance assessed with the Mann-Whitney U test. (E) Volcano plot showing differentially expressed genes in low- versus high-PHB groups. Neuronal differentiation genes NEGR1, HES1, and NGF marked (red circles). (F) GO analysis showing most GO categories significantly enriched in differentially expressed genes in low versus high PHB–expressing tumors. P values calculated with Fisher’s exact test. (G) GSEA indicating enrichment and upregulation of genes involved in neuronal differentiation, neuron development, and neurogenesis in patient tumors expressing PHB at low levels. P values calculated with Fisher’s exact test.