ΔNp63 Inhibits Oxidative Stress-Induced Cell Death, Including Ferroptosis, and Cooperates with the BCL-2 Family to Promote Clonogenic Survival

Gary X. Wang, Ho Chou Tu, Yiyu Dong, Anders Jacobsen Skanderup, Yufeng Wang, Shugaku Takeda, Yogesh Tengarai Ganesan, Song Han, Han Liu, James J. Hsieh, Emily H. Cheng

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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.

Original languageEnglish
Pages (from-to)2926-2939
Number of pages14
JournalCell Reports
Volume21
Issue number10
DOIs
StatePublished - Dec 5 2017

Keywords

  • BCL-2
  • ROS
  • TP63
  • apoptosis
  • ferroptosis
  • glutathione metabolism
  • necrosis
  • oxidative stress
  • programmed necrotic death
  • redox

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