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

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.

Molecular Mechanisms of Hepatoblastoma

“…75 Moreover, the importance of Myc proteins in HB was further underlined by the finding that treatment with bromodomain and extraterminal motif (BET) and Aurora inhibitors targeting Myc hinders the growth of HB cells in vitro. 76…”

DNA methylation in Hepatoblastoma-a literature review

“…In pediatric HB, MYCN is overexpressed, and its promoter region is hypomethylated. The use of the MYCN inhibitors alisertib (MLN8237) and JQ1 can inhibit tumor growth, indicating that the MYCN gene is also involved in the tumorigenic process in HB [66] (Table 1).…”

A retrospective study of clinical features and outcome in patients with refractory or recurrent hepatoblastoma: A single institution experience

“…28 Some target therapies or immunotherapy using cixutumumab, pazopanib, alisertib, sorafenib and glypican-3-derived peptide vaccines have been applied in clinical trials but more acceptable results are needed. 12e14, 29,30 Surgery has the most essential role in the management of HB. It relies on a skillful surgeon and a liver transplant expert.…”