Document Type

Article

Publication Date

8-15-2023

Publication Title

Biology

Abstract

Human neuroblastoma (NB) is the most common childhood extracranial tumor arising from the sympathetic nervous system. It is also a clinically heterogeneous disease that ranges from spontaneous regression to high-risk stage 4 disease. The cause of this disease remains elusive. However, the amplification of NMYC oncogene occurred in roughly 30% of NB patients, which strongly correlated with the advanced stage of disease subtype and the worse prognosis status. We discovered that N-Myc oncoprotein binds and activates INSM1, a zinc-finger transcription factor of neuroendocrine tumors. We also found that INSM1 modulates N-Myc stability mediated through PI3K/AKT/GSK3β signaling pathway. Therefore, INSM1 emerges as a critical co-player with N-Myc in facilitating NB tumor cell growth and sustaining the advanced stage of malignancy. Using an INSM1-promoter driven luciferase screening-platform, we have recently identified fifteen small molecules that negatively regulate INSM1 expression. Interestingly, the identified small molecules can be divided into four large groups of compounds such as cell signaling inhibitor, DNA/RNA inhibitor, HDAC inhibitor, and cardiac glycoside. These findings support the presence of a unique mechanism associated with INSM1 and N-Myc interplay, which is critical in regulating NB tumor cell growth. We discuss the feasibility of identifying novel or repurposing small molecules targeting INSM1 as a potential treatment option for high-risk NB.

PubMed ID

37627018

Volume

12

Issue

8

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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