Ubiquitin-protein ligase E3C maintains non-small-cell lung cancer sternness by targeting AHNAK-p53 complex
Ubiquitin-protein ligase E3C maintains non-small-cell lung cancer sternness by targeting AHNAK-p53 complex
复制标题
泛素蛋白连接酶 E3C 通过靶向 AHNAK-p53 复合物维持非小细胞肺癌干性。
DOI：
10.1016/j.canlet.2018.11.029
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Ge, Di
中科院分区：
文献类型：
--
作者：
Gu, Jie;Mao, Wei;Ge, Di
肿瘤斯特恩样细胞(CSCs)被认为是肿瘤发生、转移和耐药的来源，限制了目前的癌症治疗。阐明控制CSC特性的分子模式对于优化治疗方法是必要的。在这项研究中，我们发现泛素蛋白连接酶E3C(UBE3C)介导的泛素化是维持非小细胞肺癌(NSCLC)CSC特性的关键翻译后机制。UBE3C在干细胞样非小细胞肺癌细胞中高表达，并作为烈性增强剂。在体内和体外，UBE3C基因的敲除降低了非小细胞肺癌的严谨性和肿瘤的发生。我们进一步确定AHNAK是一种新的UBE3C底物，发现UBE3C通过泛素化和促进AHNAK的降解来保持其严谨性。AHNAK作为辅助因子协助P53与严厉相关基因启动子结合抑制转录，随后UBE3C过表达下调AHNAK解除了P53对基因表达的抑制，导致茎的增强。对208例非小细胞肺癌患者的临床意义进行了研究，证实UBE3C活性降低和AHNAK蛋白水平升高与生存期延长有关。总之，研究结果首次揭示了UBE3C介导的泛素化作为CSCs的关键调节因子的全球特征，结果表明AHNAK-P53复合体参与其中。
Cancer stern-like cells (CSCs) are regarded as sources of tumorigenesis, metastasis, and drug resistance, which limits current cancer therapies. Elucidating the molecular modes governing CSC properties is necessary to optimize therapeutic approaches. In this study, we discovered that ubiquitin-protein ligase E3C (UBE3C)-mediated ubiquitination is a key posttranslational mechanism involved in maintaining CSC properties of non-small-cell lung cancer (NSCLC). UBE3C was overexpressed in stem-like NSCLC cells and acted as a sternness enhancer. Knockdown of UBE3C reduced NSCLC sternness and tumorigenesis both in vivo and in vitro. We further identified AHNAK as a novel UBE3C substrate, finding that UBE3C maintained sternness by ubiquitinating and promoting AHNAK degradation. AHNAK functioned as a cofactor assisting p53 binding to sternness-related gene promoters to inhibit transcription, Subsequent downregulation of AHNAK by UBE3C overexpression removed p53 -mediated inhibition of gene expression, resulting in enhanced stemness. Clinical significance was investigated in 208 NSCLC patients and confirmed that attenuated UBE3C activity and elevated AHNAK protein levels correlated with extended survival time. Collectively, findings reveal the first global characterization of UBE3C-mediated ubiquitination as a key regulator of CSCs, with results suggesting involvement of the AHNAK-p53 complex.