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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

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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 3

PHB knockdown impairs ERK activation, reduces cell viability, slows cell cycle progression, and induces apoptosis in neuroblastoma cells.

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PHB knockdown impairs ERK activation, reduces cell viability, slows cell...
(A) Western blot analysis displaying quantities of phosphorylated ERK1/2 at T202/Y204 in IMR-5/75 cells. ERK1/2 results are representative of 3 independent experiments. (B) IMR-5/75 cell proliferation following PHB knockdown as measured with the RTCA iCelligence system. Each condition was tested in duplicate. (C) FACS plots showing IMR-5/75 cell cycle distribution following PHB knockdown. (D) Quantification of cells in S phase after PHB knockdown. Data represent mean ± SD. *P < 0.001, 2-tailed t test. (E) Cell viability of IMR-5/75 cells expressing ectopic PHB-V5 following transduction of an shRNA against the 3′ UTR of PHB. Viability measured with the CellTiter-Glo luminescent viability assay. Data represent mean ± SEM. *P < 0.001, 2-tailed t test. (F) Representative FACS plots of TUNEL-stained IMR-5/75 neuroblastoma cells after PHB knockdown. (G) Quantification of TUNEL-positive cells after PHB knockdown. Data represent mean ± SD. *P < 0.001, 2-tailed t test. Three technical replicates shown. Bonferroni’s correction was applied to account for multiple comparisons.

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