An iron-dependent form of cell death called ferroptosis has been implicated as a component of the tumour-suppressor activity of p53, providing fresh insight into how this protein prevents cancer development. See Article p.57
The gene that encodes the p53 tumour-suppressor protein is the most commonly mutated gene in human cancers1. Indeed, p53 is inactivated in more than half of all cancers, reflecting the fact that it provides a crucial brake to cancer development, and that incapacitating p53 is often a requisite step for the emergence of cancer. However, despite years of research, our understanding of how p53 performs its job remains far from complete. In this issue, Jiang et al.2 (page 57) uncover a previously unknown role for p53 in regulating a type of cell death dubbed ferroptosis, completing one more piece of the p53 puzzle.
Conventionally, p53 is thought of as a sentinel for DNA damage. In this role as a guardian of the genome, p53 responds to DNA damage either by putting the brakes on proliferation, allowing cells to pause and repair damaged DNA before dividing, or by driving a form of cell suicide called apoptosis, both of which protect against the accumulation of mutant cells that have the potential to fuel cancer development3,4. The protein fulfils this responsibility in large part by serving as a transcription factor that, among its many target genes, modulates the expression of genes encoding proteins that inhibit cell division or induce apoptosis4.
Although this regulatory role as a guardian of the genome seems to account for p53's tumour-suppressor function, several studies have altered our thinking about how p53 represses cancer development. A set of papers (including one from the authors of the current study) provided pivotal evidence that p53-mediated apoptosis and proliferative arrest in response to DNA-damage signals are dispensable for tumour suppression5,6,7. These studies illuminated the functions of p53 that are not essential for tumour suppression, but failed to definitively reveal which p53 functions are required. Jiang and colleagues' latest study sheds light on this issue.
The authors use a mutated form of p53 called p533, which carries alterations at several key sites in its DNA-targeting region. As such, p533 has an impaired ability to activate many of p53's target genes, including those responsible for the protein's anti-proliferative and pro-apoptotic activity. The mutated protein nonetheless suppresses spontaneous tumour development in mice6 — but how? The authors embark on an unbiased quest to answer this question by searching for potential mediators of p53 tumour-suppressor function. They identify SLC7A11 as a gene whose expression is repressed by both p53 and p533.
SLC7A11 is a cell-surface, amino-acid transporter protein that dampens the production of reactive oxygen species (ROS), which can wreak havoc in a cell by inducing damage8. In particular, by limiting ROS accumulation, SLC7A11 inhibits ferroptosis, a form of non-apoptotic cell death triggered by the iron-dependent production of ROS9 (Fig. 1). Jiang et al. show that both p53 and p533 can stimulate ferroptosis in vitro in response to the ferroptosis-activating agent erastin, and that this response can be inhibited by the overproduction of SLC7A11. This contrasts starkly with the inability of p533 to regulate classical p53 functions, and suggests that the ability to induce ferroptosis could account for the function of p533 in mice.
To test this hypothesis, the authors analyse mouse embryos carrying p533 but lacking the protein Mdm2, an essential inhibitor of p53. These mutant embryos normally die as a result of hyperactive p53 signalling, but the authors show that inhibiting ferroptosis imparts some protection against this lethality. These experiments provide evidence that ferroptosis contributes to p53 activity in vivo, in this case promoting embryonic lethality.
Expanding this analysis to cancer development, Jiang and colleagues next show that overexpression of SLC7A11 overcomes the tumour-suppressor effects of p533 in tumours transplanted into mice. This suggests that repression of SLC7A11 transcription is necessary for p533-mediated tumour suppression, and, moreover, that p533 suppresses tumour growth at least in part through ferroptosis. However, it remains unclear whether p53-mediated activation of ferroptosis is a front-line tumour-suppressive response or whether it primarily provides a back-up mechanism when other p53 functions are crippled, as in the p533 mutant.
This study unveils a new pathway for p53-dependent tumour suppression. However, many questions remain. For instance, it is still unknown whether ferroptosis is a general mechanism that operates in all tumour types or whether it has a more selective function, suppressing cancers that originate from specific tissues. It is also not yet clear which p53-activating signals — such as expression of cancer-promoting genes or deprivation of nutrients — activate ferroptosis in vivo. The roles of other p53 target genes in ferroptosis must also be defined.
In the broader landscape, it will be imperative to determine which other p53-dependent processes contribute to tumour suppression and what their context dependencies may be10. Although DNA-damage-induced apoptosis and cell-cycle arrest have been deemed to be dispensable for tumour suppression, this does not preclude a role for these responses in some settings. Finally, the finding that inducing ferroptosis by using an erastin analogue delays the growth of p53-expressing tumours in a mouse transplant model11 suggests that activating ferroptosis may be a promising therapeutic strategy for treating tumours in which p53 activity is retained, a possibility that warrants further investigation.Footnote 1
Freed-Pastor, W. A. & Prives, C. Genes Dev. 26, 1268–1286 (2012).
Jiang, L. et al. Nature 520, 57–62 (2015).
Lane, D. P. Nature 358, 15–16 (1992).
Vousden, K. H. & Prives, C. Cell 137, 413–431 (2009).
Brady, C. A. et al. Cell 145, 571–583 (2011).
Li, T. et al. Cell 149, 1269–1283 (2012).
Valente, L. J. et al. Cell Rep. 3, 1339–1345 (2013).
Conrad, M. & Sato, H. Amino Acids 42, 231–246 (2012).
Dixon, S. J. et al. Cell 149, 1060–1072 (2012).
Bieging, K. T., Mello, S. S. & Attardi, L. D. Nature Rev. Cancer 14, 359–370 (2014).
Yang, W. S. et al. Cell 156, 317–331 (2014).
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