Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells
| Autor: | Kristina Becker, Beate Häberle, R Kappler, Corinna Eberherr, Dietrich von Schweinitz, Christian Vokuhl, Alexander M. Beck |
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| Rok vydání: | 2019 |
| Předmět: |
Hepatoblastoma
Male 0301 basic medicine Cancer Research Adolescent Population Biology Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Biomarkers Tumor medicine Humans RNA Antisense Epigenetics Child education neoplasms Early Detection of Cancer Cell Proliferation Regulation of gene expression N-Myc Proto-Oncogene Protein education.field_of_study Gene knockdown Oncogene Liver Neoplasms Infant Newborn Infant Azepines DNA Methylation Triazoles Cell cycle medicine.disease Molecular medicine Neoplasm Proteins Up-Regulation Gene Expression Regulation Neoplastic Pyrimidines 030104 developmental biology Oncology Child Preschool 030220 oncology & carcinogenesis Cancer research Female |
| Zdroj: | International Journal of Oncology. |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2019.4741 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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