Department of Thoracic Surgery, The Affiliated Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China; Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences, and Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.
Cancer Lett. 2019 Feb 28;443:125-134. doi: 10.1016/j.canlet.2018.11.029. Epub 2018 Nov 29.
Cancer stem-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 stemness enhancer. Knockdown of UBE3C reduced NSCLC stemness and tumorigenesis both in vivo and in vitro. We further identified AHNAK as a novel UBE3C substrate, finding that UBE3C maintained stemness by ubiquitinating and promoting AHNAK degradation. AHNAK functioned as a cofactor assisting p53 binding to stemness-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.
癌症干细胞 (CSCs) 被认为是肿瘤发生、转移和耐药的根源，这限制了当前的癌症治疗方法。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 在类干细胞 NSCLC 细胞中过表达，并作为干细胞增强因子发挥作用。UBE3C 的敲低减少了 NSCLC 干细胞特性和体内外的肿瘤发生。我们进一步鉴定出 AHNAK 是 UBE3C 的一种新型底物，发现 UBE3C 通过泛素化和促进 AHNAK 降解来维持干细胞特性。AHNAK 作为辅助 p53 结合到与干细胞相关的基因启动子以抑制转录的共因子发挥作用。随后，UBE3C 过表达下调 AHNAK，消除了 p53 对基因表达的抑制，从而增强了干细胞特性。在 208 名 NSCLC 患者中进行了临床意义的研究，并证实减弱的 UBE3C 活性和升高的 AHNAK 蛋白水平与延长的生存时间相关。总之，研究结果揭示了 UBE3C 介导的泛素化作为 CSCs 的关键调节剂的首次全面特征，并表明 AHNAK-p53 复合物的参与。
