NRF2 Is a Major Target of ARF in P53-Independent Tumor Suppression

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Oct 7

PMID 28985506

Citations 166

Authors

Delin Chen

Omid Tavana

Bo Chu

Luke Erber

Yue Chen

Richard Baer

Wei Gu

Affiliations

Soon will be listed here.

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.

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