AUTHOR=Liu Tao , Gu Lubing , Wu Zhongzhi , Albadari Najah , Li Wei , Zhou Muxiang 

TITLE=MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1058726

DOI=10.3389/fonc.2022.1058726

ISSN=2234-943X

ABSTRACT=<p>Amplification of the <italic>MYCN</italic> gene leads to its overexpression at both the mRNA and protein levels. Overexpression of <italic>MYCN</italic> mRNA may also have an important role in promoting neuroblastoma (NB) beyond the translation of MYCN protein. In the present study, we report a small molecule compound (MX25-1) that was able to bind to the 3’UTR of <italic>MYCN</italic> mRNA and induce <italic>MYCN</italic> mRNA degradation; this resulted in potent cell-growth inhibition and cell death specifically in <italic>MYCN</italic>-amplified or <italic>MYCN</italic> 3’UTR overexpressing NB cells. To evaluate the role of <italic>MYCN</italic> 3’UTR-mediated signals in contributing to the anticancer activity of MX25-1, we examined the status and activation of the tumor suppressor microRNA (miRNA) let-7, which is a target of <italic>MYCN</italic> 3’UTR in <italic>MYCN</italic>-amplified NB. We first observed that overexpression of <italic>MYCN</italic> mRNA was associated with high-level expression of the let-7 oncogenic targets DICER1, ARID3B and HMGA2. Following <italic>MYCN</italic> mRNA degradation, the expression of DICER1, ARID3B and HMGA2 was downregulated in MX25-1-treated cells. Inhibition of let-7 reversed the downregulation of these oncogenic mRNAs and significantly increased resistance of NB cells to MX25-1. Our results from this study supported the notion that overexpression of <italic>MYCN</italic> mRNA due to gene amplification has an independent function in NB cell growth and disease progression and suggest that targeting <italic>MYCN</italic> mRNA may represent an attractive strategy for therapy of <italic>MYCN</italic> amplified NB, both by inhibiting MYCN’s cell-survival effects and activating the tumor-suppressor effect of let-7.</p>