Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, Chongqing, China.
Cell Death Dis. 2021 Jan 19;12(1):98. doi: 10.1038/s41419-021-03392-6.
It has been postulated that cancer stem cells (CSCs) are involved in all aspects of human cancer, although the mechanisms governing the regulation of CSC self-renewal in the cancer state remain poorly defined. In the literature, both the pro- and anti-oncogenic activities of autophagy have been demonstrated and are context-dependent. Mounting evidence has shown augmentation of CSC stemness by autophagy, yet mechanistic characterization and understanding are lacking. In the present study, by generating stable human lung CSC cell lines with the wild-type TP53 (A549), as well as cell lines in which TP53 was deleted (H1229), we show, for the first time, that autophagy augments the stemness of lung CSCs by degrading ubiquitinated p53. Furthermore, Zeb1 is required for TP53 regulation of CSC self-renewal. Moreover, TCGA data mining and analysis show that Atg5 and Zeb1 are poor prognostic markers of lung cancer. In summary, this study has elucidated a new CSC-based mechanism underlying the oncogenic activity of autophagy and the tumor suppressor activity of p53 in cancer, i.e., CSCs can exploit the autophagy-p53-Zeb1 axis for self-renewal, oncogenesis, and progression.
已经提出，癌症干细胞（CSCs）参与了人类癌症的各个方面，尽管控制癌症状态下 CSC 自我更新的机制仍未明确定义。文献中已经证明了自噬的促癌和抑癌活性，并且具有上下文依赖性。越来越多的证据表明自噬增强了 CSC 的干性，但缺乏机制表征和理解。在本研究中，通过生成具有野生型 TP53（A549）的稳定人肺 CSC 细胞系，以及缺失 TP53 的细胞系（H1229），我们首次表明，自噬通过降解泛素化的 p53 来增强肺 CSC 的干性。此外，Zeb1 是 TP53 调节 CSC 自我更新所必需的。此外，TCGA 数据挖掘和分析表明，Atg5 和 Zeb1 是肺癌不良预后的标志物。总之，本研究阐明了自噬的致癌活性和 p53 在癌症中的肿瘤抑制活性的基于 CSC 的新机制，即 CSCs 可以利用自噬-p53-Zeb1 轴进行自我更新、致癌和进展。
