LncRNA NRON promotes tumorigenesis by enhancing MDM2 activity toward tumor suppressor substrates
LncRNA NRON promotes tumorigenesis by enhancing MDM2 activity toward tumor suppressor substrates
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DOI：
10.15252/embj.2022112414
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发表时间：
2023-06-29
期刊：
影响因子：
11.4
通讯作者：
Luo, Man-Li
中科院分区：
文献类型：
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作者：
Guo, Qiannan;Li, Yihui;Luo, Man-Li
E3连接酶MDM2通过诱导泛素介导的P53和其他肿瘤抑制蛋白的降解来促进肿瘤生长和进展。在这里，我们确定了一个MDM2相互作用的lncRNA NRON，它通过抑制P53依赖性和非依赖性途径来促进肿瘤形成。NRON分别通过两个不同的茎环与MDM2和MDMX（MDM4）结合，并诱导其异源二聚化，从而增强MDM2对其肿瘤抑制底物（包括P53、RB 1和NFAT 1）的E3连接酶活性。NRON敲低在体外和体内显著抑制肿瘤细胞生长。更重要的是，NRON过表达通过诱导体外锚定非依赖性生长和促进免疫功能低下小鼠的肿瘤形成来促进致癌转化。临床上，NRON表达与乳腺癌患者的不良临床结局显著相关。总之，我们的数据揭示了lncRNA通过抑制多种肿瘤抑制蛋白诱导上皮细胞恶性转化的关键作用。
The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor-suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53-dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem-loops, respectively, and induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 toward its tumor-suppressing substrates, including P53, RB1, and NFAT1. NRON knockdown dramatically inhibits tumor cell growth in vitro and in vivo. More importantly, NRON overexpression promotes oncogenic transformation by inducing anchorage-independent growth in vitro and facilitating tumor formation in immunocompromised mice. Clinically, NRON expression is significantly associated with poor clinical outcome in breast cancer patients. Together, our data uncover a pivotal role of lncRNA that induces malignant transformation of epithelial cells by inhibiting multiple tumor suppressor proteins.