Journal
CELL DEATH & DISEASE
Volume 12, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-03392-6
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Funding
- National Natural Science Fund [82073277, 81672908]
- Science and Technology Project Affiliated to the Education Department of Chongqing [KJQN201800426]
- Natural Science Fund of Chongqing [cstc2019jcyj-msxmX0868]
- Science and Technology Project of Chongqing Yuzhong District [20200110]
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This study elucidates a new mechanism underlying the oncogenic activity of autophagy in cancer stem cells, showing that autophagy enhances the stemness of lung CSCs by degrading p53, and that Zeb1 is essential for TP53 regulation of CSC self-renewal. Additionally, Atg5 and Zeb1 are identified as poor prognostic markers of lung cancer through TCGA data mining.
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.
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