NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression

Delin Chen, Omid Tavana, Bo Chu, Luke Erber, Yue Chen, Richard Baer, Wei Gu

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Although ARF can suppress tumor growth by activating p53 function, the mechanisms by which it suppresses tumor growth independently of p53 are not well understood. Here, we identified ARF as a key regulator of nuclear factor E2-related factor 2 (NRF2) through complex purification. ARF inhibits the ability of NRF2 to transcriptionally activate its target genes, including SLC7A11, a component of the cystine/glutamate antiporter that regulates reactive oxygen species (ROS)-induced ferroptosis. As a consequence, ARF expression sensitizes cells to ferroptosis in a p53-independent manner while ARF depletion induces NRF2 activation and promotes cancer cell survival in response to oxidative stress. Moreover, the ability of ARF to induce p53-independent tumor growth suppression in mouse xenograft models is significantly abrogated upon NRF2 overexpression. These results demonstrate that NRF2 is a major target of p53-independent tumor suppression by ARF and also suggest that the ARF-NRF2 interaction acts as a new checkpoint for oxidative stress responses. Chen et al. identified ARF as a key regulator of NRF2-mediated activation of SLC7A11, a component of the cystine/glutamate antiporter that regulates reactive oxygen species (ROS)-induced ferroptosis. They showed that the ARF-NRF2 interaction is critical for p53-independent ferroptosis and tumor suppression induced by ARF.

Original languageEnglish (US)
Pages (from-to)224-232.e4
JournalMolecular Cell
Volume68
Issue number1
DOIs
StatePublished - Oct 5 2017

Bibliographical note

Funding Information:
We thank Dr. Donna Zhang and Dr. Jason Weber for providing critical reagents for this study. This work was supported by the National Cancer Institute of the NIH under awards 5R01CA169246 , 5RO1CA190477 , 5RO1CA085533 , and 5RO1CA216884 to W.G, and 5R01-CA172272 to R.B. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Keywords

  • ARF
  • NRF2
  • ROS
  • ferroptosis
  • oxidative stress
  • p53
  • transcriptional regulation

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