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p21 shapes cancer evolution

Nature Cell Biology volume 18, pages 722–724 (2016)Cite this article

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Although known to induce cellular senescence, an important tumour suppressor mechanism, mutation of CDKN1A — the gene encoding p21 (also known as WAF1 or CIP1) — is rare in human cancers. Now, a study reports a previously unappreciated oncogenic effect of p21 overexpression that shapes cancer genome evolution through induction of replication stress.

p21-dependent suppression of cell proliferation by inhibition of cyclin–kinase complexes, PCNA, transcription factors and coactivators are regarded as mechanisms that impair the formation of tumours in response to p53 activation. However, p21 deletion does not abrogate tumour suppression mediated by p53-dependent regulation of metabolism and antioxidant function3. Instead, p21 contributes to leukaemia cancer growth by slowing the accumulation of DNA damage in leukaemia stem cells and thus maintaining their capacity to self-renew4. Moreover, p21-dependent activation of cyclin D–CDK4/6 complexes, inhibition of apoptosis and induction of cell motility contribute to p21-dependent promotion of tumorigenesis, which has been observed in several mouse models5. Interestingly, the tumour-suppressive activities of p21 are associated with its nuclear localization, whereas its localization in the cytoplasm associates with oncogenic effects (Fig. 1)2. Intriguingly, mutations or deletions of the CDKN1A gene are very rare in human tumours. Instead, the inactivation of p21-dependent tumour-suppressive functions and activation of its oncogenic features commonly occur by its relocation from the nucleus to the cytoplasm; overexpression or cytoplasmic localization of p21 correlates with poor prognosis in a broad range of tumours6. But a completely different oncogenic mechanism of nuclear p21 is now presented by Galanos et al.7 in this issue of Nature Cell Biology. The authors demonstrate that a subset of p53-deficient cancer cells and tumours exhibit chronic overexpression of nuclear p21, which in turn leads to deregulation of replication licensing, replication stress and genomic instability.

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Figure 1: p21 regulates various cellular programs by different mechanisms.
Figure 2: The model proposed by Galanos et al.

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Authors and Affiliations

  1. Vasily S. Romanov and K. Lenhard Rudolph are at the Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany,

    Vasily S. Romanov & K. Lenhard Rudolph

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  1. Vasily S. Romanov
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  2. K. Lenhard Rudolph
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Correspondence to K. Lenhard Rudolph.

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Romanov, V., Rudolph, K. p21 shapes cancer evolution. Nat Cell Biol 18, 722–724 (2016). https://doi.org/10.1038/ncb3382

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