A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways

Neuroblastoma (NB) is the most common extracranial tumor in children. In NB, the loss of p53 function is primarily due to cytoplasmic sequestration rather than mutation. Ubiquitin-conjugating enzyme E2 N (UBE2N), also known as Ubc13, is an E2 enzyme that facilitates the formation of monomeric p53, leading to its cytoplasmic translocation and subsequent inactivation. Therefore, inhibiting UBE2N may restore p53 function by promoting its nuclear accumulation. In this study, we demonstrate that NSC697923, a novel UBE2N inhibitor, exhibits potent cytotoxicity in a panel of NB cell lines, evidenced by its ability to induce apoptosis. In p53 wild-type NB cells, NSC697923 triggered the nuclear accumulation of p53, enhancing its transcriptional activity and tumor-suppressing function. In contrast, in p53 mutant NB cells, NSC697923 induced cell death through activation of the JNK pathway, an effect that could be reversed by blocking JNK activity with the selective inhibitor SP600125. Notably, NSC697923 also inhibited the growth of the chemoresistant LA-N-6 NB cell line more effectively than conventional chemotherapy agents like doxorubicin and etoposide. Additionally, NSC697923 demonstrated antitumor efficacy in vivo in NB orthotopic xenografts. Together, these findings suggest that UBE2N is a promising therapeutic target in NB and support the potential use of UBE2N inhibitors such as NSC697923 as a novel treatment option for NB patients.