转录因子MYCN在多种癌症中经常发生扩增和过度表达，其中包括高风险神经母细胞瘤（NB），并促进肿瘤细胞的增殖、存活和迁移。因此，MYCN被认为是一个“无法靶向”的目标，因此正在追求对其上游调控因子进行选择性抑制，因为这些上游调控因子被认为是引发其表达的重要部分。因此，探索MYCN的转录和翻译后修饰的上游调控因子具有重要意义。本文报告了BRCA1相关蛋白1（BAP1）通过直接结合MYCN蛋白而促进其去泛素化和稳定化的功能。此外，BAP1敲除在体外和体内抑制了NB肿瘤细胞的生长和迁移，并且通过外源性MYCN的过量表达可以部分恢复这种抑制作用。重要的是，BAP1缺失使细胞耐受溴域和超终端蛋白（BET）抑制剂JQ1和Aurora A激酶抑制剂Alisertib。此外，NB组织芯片的免疫组织化学（IHC）结果证实了BAP1与MYCN蛋白的阳性相关性。总之，我们的研究不仅揭示了BAP1通过稳定MYCN表现出的致癌功能，还揭示了NB中对MYCN的翻译后调控的关键机制。我们的发现进一步表明BAP1可能是MYCN扩增神经母细胞瘤的一个潜在治疗靶点。© 2023. 作者。

The transcription factor MYCN is frequently amplified and overexpressed in a variety of cancers including high-risk neuroblastoma (NB) and promotes tumor cell proliferation, survival, and migration. Therefore, MYCN is being pursued as an attractive therapeutic target for selective inhibition of its upstream regulators because MYCN is considered a "undruggable" target. Thus, it is important to explore the upstream regulators for the transcription and post-translational modification of MYCN. Here, we report that BRCA1-associated protein-1 (BAP1) promotes deubiquitination and subsequent stabilization of MYCN by directly binding to MYCN protein. Furthermore, BAP1 knockdown inhibits NB tumor cells growth and migration in vitro and in vivo, which can be rescued partially by ectopic expression of MYCN. Importantly, depletion of BAP1 confers cellular resistance to bromodomain and extraterminal (BET) protein inhibitor JQ1 and Aurora A kinase inhibitor Alisertib. Furthermore, IHC results of NB tissue array confirmed the positive correlation between BAP1 and MYCN protein. Altogether, our work not only uncovers an oncogenic function of BAP1 by stabilizing MYCN, but also reveals a critical mechanism for the post-translational regulation of MYCN in NB. Our findings further indicate that BAP1 could be a potential therapeutic target for MYCN-amplified neuroblastoma.© 2023. The Author(s).