Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells

Eberherr,Corinna; Beck,Alexander; Vokuhl,Christian; Becker,Kristina; Häberle,Beate; Von Schweinitz,Dietrich; Kappler,Roland

doi:10.3892/ijo.2019.4741

Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells

Authors:
- Corinna Eberherr
- Alexander Beck
- Christian Vokuhl
- Kristina Becker
- Beate Häberle
- Dietrich Von Schweinitz
- Roland Kappler
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Affiliations: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, D‑80337 Munich, Germany, Institute of Paidopathology, Pediatric Tumor Registry, Christian‑Albrecht's‑University Kiel, D‑24105 Kiel, Germany
Published online on: March 5, 2019 https://doi.org/10.3892/ijo.2019.4741
Pages: 1853-1863

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Abstract

Hepatoblastoma (HB) is the most common liver tumor in children under the age of 3 years worldwide. While many patients achieve good outcomes with surgical resection and conventional chemotherapy, there is still a high‑risk population that exhibits a poor treatment response and unfavorable prognosis, which warrants the search for novel treatment options. In recent years, it has become clear that genetic events alone are not sufficient to explain the aggressive phenotype of this embryonal malignancy. Instead, epigenetic modifications and aberrant gene expression seem to be key drivers of HB. In the present study, expression analyses such as reverse transcription‑quantitative polymerase chain reaction revealed that the oncogene, MYCN proto‑oncogene basic‑helix‑loop‑helix transcription factor (MYCN) was upregulated in HB and other pediatric liver tumors, due to the transcriptional activity of its antisense transcript MYCN opposite strand (MYCNOS). Pyrosequencing demonstrated the hypomethylated regions in the promoter of MYCN and MYCNOS, suggesting that an epigenetic mechanism may underlie the induction of aberrant expression. Transient MYCN knockdown in HB cells resulted in growth inhibition over time. In addition, treating HB cells with the MYCN inhibitors JQ1 and MLN8237 led to the significant downregulation of MYCN either at the mRNA or protein levels, respectively. The underlying mechanism of action of the two inhibitors was revealed to be associated with the induction of dose‑dependent growth arrest, by arresting cells at either the G1/G0 or G2 phase. Furthermore, MLN8237 and JQ1 were able to cause spindle disturbances and/or apoptosis in HB cells. The present results suggest that MYCN may be a promising biomarker for HB and a potential therapeutic target in patients with tumors overexpressing MYCN.

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