{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMYCN is a central oncogenic transcription factor whose amplification and aberrant over‐expression drive malignant progression in a variety of tumors—including pediatric neuroblastoma, medulloblastoma, neuroendocrine prostate cancer, and even certain lymphomas. Its deregulated expression, often occurring in conjunction with MYC family members and developmental regulators such as LIN28B, reprograms normal cellular programs by activating metastasis‐promoting microRNAs (for example, miR‑9) and blocking differentiation. Moreover, MYCN overexpression can induce proliferative signalling while counteracting apoptotic checkpoints, thereby contributing to aggressive tumor behavior."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the transcriptional level, MYCN directly binds to canonical E‑box motifs to orchestrate a wide array of downstream gene expression programs. Through its regulatory activity, MYCN upregulates genes that inhibit p53‐mediated apoptosis (for example, via induction of MDM2) and simultaneously modulates critical microRNAs—such as miR‑34a, members of the let‑7 family, and miR‑184—that collectively govern cell cycle progression, differentiation, and metabolic flux. In addition, MYCN‐dependent transcription is linked to changes in polyamine biosynthesis and the expression of metabolic regulators, underscoring its role in establishing the oncogenic transcriptome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPost‐translational regulation is equally pivotal to MYCN function. Key kinases and ubiquitin ligases—notably Aurora‑A, PLK1, and components of the PI3K/AKT pathway—modulate MYCN protein stability by either impeding its degradation via the ubiquitin–proteasome system or by direct structural interactions that protect it from turnover. The disruption of these stabilizing interactions, for instance via Aurora‑A inhibitors or by interfering with PLK1 function, has demonstrated potent antitumor effects, thereby revealing attractive therapeutic strategies to counteract MYCN‐driven tumor growth."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in gene transcription and protein stability, MYCN exerts far‐reaching effects on chromatin architecture and cellular metabolism. It participates in enhancer hijacking events and drives global euchromatin maintenance, thereby reshaping the epigenetic landscape to favor oncogenic gene expression. MYCN also reprograms metabolic pathways by promoting glutamine uptake through the induction of transporters such as ASCT2 and by enhancing aerobic glycolysis via cooperation with HIF‑1α. These multifaceted effects underline MYCN’s critical functions in tumor initiation, progression, and maintenance, and underscore its promise as a therapeutic target in cancers characterized by its dysregulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Li Ma, Jennifer Young, Harsha Prabhala, et al. 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