ΔNp63 inhibits oxidative stress-induced cell death, including ferroptosis, and cooperates with the BCL-2 family to promote clonogenic survival Journal Article


Authors: Wang, G. X.; Tu, H. C.; Dong, Y.; Skanderup, A. J.; Wang, Y.; Takeda, S.; Ganesan, Y. T.; Han, S.; Liu, H.; Hsieh, J. J.; Cheng, E. H.
Article Title: ΔNp63 inhibits oxidative stress-induced cell death, including ferroptosis, and cooperates with the BCL-2 family to promote clonogenic survival
Abstract: The BCL-2 family proteins are central regulators of apoptosis. However, cells deficient for BAX and BAK or overexpressing BCL-2 still succumb to oxidative stress upon DNA damage or matrix detachment. Here, we show that ΔNp63α overexpression protects cells from oxidative stress induced by oxidants, DNA damage, anoikis, or ferroptosis-inducing agents. Conversely, ΔNp63α deficiency increases oxidative stress. Mechanistically, ΔNp63α orchestrates redox homeostasis through transcriptional control of glutathione biogenesis, utilization, and regeneration. Analysis of a lung squamous cell carcinoma dataset from The Cancer Genome Atlas (TCGA) reveals that TP63 amplification/overexpression upregulates the glutathione metabolism pathway in primary human tumors. Strikingly, overexpression of ΔNp63α promotes clonogenic survival of p53−/−Bax−/−Bak−/− cells against DNA damage. Furthermore, co-expression of BCL-2 and ΔNp63α confers clonogenic survival against matrix detachment, disrupts the luminal clearance of mammary acini, and promotes cancer metastasis. Our findings highlight the need for a simultaneous blockade of apoptosis and oxidative stress to promote long-term cellular well-being. Apoptosis-defective cells remain vulnerable to oxidative stress, which limits long-term survival. Wang et al. identify ΔNp63α as a central regulator of redox homeostasis through transcriptional control of a tightly coupled glutathione metabolic circuit. ΔNp63α alleviates oxidative stress and cooperates with the BCL-2 family to promote both long-term cellular well-being and cancer metastasis. © 2017 The Author(s)
Keywords: human cell; nonhuman; animal cell; mouse; cell death; dna damage; cell survival; gene overexpression; protein bcl 2; metastasis; apoptosis; gene amplification; embryo; animal experiment; necrosis; protein p53; oncogene; transcription regulation; oxidative stress; cell regeneration; homeostasis; cell protection; oxidation reduction reaction; glutathione; biogenesis; clonogenesis; tp63; tp63 gene; bcl-2; protein bax; ros; protein bak; ferroptosis; redox; anoikis; human; priority journal; article; glutathione metabolism; squamous cell lung carcinoma; programmed necrotic death; deltanp63 gene
Journal Title: Cell Reports
Volume: 21
Issue: 10
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2017-12-05
Start Page: 2926
End Page: 2939
Language: English
DOI: 10.1016/j.celrep.2017.11.030
PROVIDER: scopus
PUBMED: 29212036
PMCID: PMC5915869
DOI/URL:
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Ho Chou Tu
    3 Tu
  2. Yiyu Dong
    16 Dong
  3. Shugaku Takeda
    16 Takeda
  4. Han Liu
    12 Liu
  5. Emily H Cheng
    55 Cheng
  6. Song   Han
    5 Han
  7. Gary Xiaoshi Wang
    1 Wang
  8. Yufeng Wang
    1 Wang