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

• DOI: 10.1016/j.molcel.2017.09.009
• Publication Date: 2017-10-11T06:18:34Z
• Authors: Delin Chen; Omid Tavana; Bo Chu; Luke Erber; Yue Chen; Richard Baer; Wei Gu
• Keywords: 0301 basic medicine; Osteoblasts; Amino Acid Transport System y+; NF-E2-Related Factor 2; Mice, Nude; Bone Neoplasms; Epithelial Cells; Fibroblasts; Gene Expression Regulation, Neoplastic; Mice; Oxidative Stress; 03 medical and health sciences; HEK293 Cells; Cell Line, Tumor; Animals; Cyclin-Dependent Kinase Inhibitor p18; Heterografts; Humans; Tumor Suppressor Protein p53; Reactive Oxygen Species; Cyclin-Dependent Kinase Inhibitor p16; Signal Transduction

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.