Pediatric tumors such as neuroblastoma are characterized by a genome-wide ‘transcriptional burden’, surmising the involvement of multiple alterations of gene expression. Search for master regulators of transcription whose inactivation is lethal for tumor cells identified the non-POU domain-containing octamer-binding protein (NONO), a member of the Drosophila Behavior/Human Splicing family known for the ability to form complexes with macromolecules. NONO emerges as an essential mechanism in normal neurogenesis as well as in tumor biology. In particular, NONO interactions with RNAs, largely with long non-coding MYCN transcripts, have been attributed to the aggressiveness of neuroblastoma. Broadening its significance beyond MYCN regulation, NONO guards a subset of transcription factors that comprise a core regulatory circuit, a self-sustained loop that maintains transcription. As a component of protein–protein complexes, NONO has been implicated in the control of cell cycle progression, double-strand DNA repair, and, generally, in cell survival. Altogether, the pro-oncogenic roles of NONO justify the need for its inactivation as a therapeutic strategy. However, considering NONO as a therapeutic target, its druggability is a challenge. Recent advances in the inactivation of NONO and downstream signaling with small molecular weight compounds make promising the development of pharmacological antagonists of NONO pathway(s) for neuroblastoma treatment.
神经母细胞瘤等儿科肿瘤的特征在于全基因组范围的"转录负荷"，推测涉及基因表达的多种改变。通过寻找转录主调控因子，发现其失活对肿瘤细胞具有致死作用，从而鉴定出不含POU结构域的八聚体结合蛋白（NONO）。该蛋白属于果蝇行为/人类剪接家族，以能与大分子形成复合物而闻名。NONO在正常神经发生和肿瘤生物学中均表现为关键机制。特别是NONO与RNA（主要是长链非编码MYCN转录本）的相互作用，被认为是神经母细胞瘤侵袭性的成因。除MYCN调控外，NONO更广泛地守护着构成核心调控回路（一个维持转录的自我维持循环）的转录因子亚群。作为蛋白质-蛋白质复合物的组成部分，NONO参与细胞周期进程调控、双链DNA修复，并普遍影响细胞存活。总之，NONO的促癌作用证明其失活作为治疗策略的必要性。然而，将NONO视为治疗靶点时，其成药性面临挑战。近期在使用小分子化合物失活NONO及其下游信号传导方面取得的进展，为开发NONO通路药理拮抗剂治疗神经母细胞瘤带来了希望。
Saying “Yes” to NONO: A Therapeutic Target for Neuroblastoma and Beyond
肿瘤(癌症)患者之家