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  • Review Article
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KLF4, p21 and context-dependent opposing forces in cancer

Nature Reviews Cancer volume 6, pages 11–23 (2006)Cite this article

Key Points

  • Krüppel-like transcription factors (KLFs) regulate the expression of many genes, including those that are involved in differentiation and cell-cycle arrest.

  • One KLF family member, KLF4, possesses tumour-suppressor-like properties, as the gene that encodes it is deleted or methylated (silenced) in human gastrointestinal tract tumours. In mice, deletion of Klf4 in the gastric compartment induces hyperplasia and polyps.

  • Ectopic expression of KLF4 induces cell-cycle arrest in a p21-dependent manner.

  • KLF4 also seems to function as a dominant oncogene, as it is often overexpressed in human breast tumours and squamous cell carcinomas, and can also contribute to oncogenic transformation of cultured cells.

  • Loss of p21 is sufficient to convert KLF4 from an inhibitor of proliferation into a transforming oncogene in vitro.

  • p21 might represent a nodal point for signals from multiple factors with opposing, context-dependent functions in cancer, including transforming growth factor-β, Notch, Runx and Ras.

  • Although CDKN1A (cyclin-dependent kinase inhibitor 1A, the gene that encodes p21) is a target gene of many key tumour-suppressor pathways, it is not often lost or mutated in human tumours.

  • p21 itself also possesses opposing functions that might both counteract and contribute to cancer progression.

  • Partial, but not complete, loss of p21 might provide a selective advantage to tumour cells, which could be related to the proposed roles for p21 in suppressing apoptosis and inducing cell-cycle arrest.

Abstract

Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4, can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?

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Figure 1: p21 in cell-cycle regulation and tumour suppression.
Figure 2: Opposing effects of KLF4 in tumorigenesis.
Figure 3: A model for oncogene collaboration based on mutual inhibition of anti-proliferative signalling.
Figure 4: p21 and DNA damage signalling.
Figure 5: KLF4, a target for multiple tumour-suppressor pathways?
Figure 6: Cellular levels of p21 regulation.

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Acknowledgements

We are grateful to M. Ewen and A. Rustgi for sharing unpublished data, S. Friedman for helpful suggestions and M. van Lohuizen for critical reading of the manuscript. B.D.R. and D.S.P. are supported by grants from the Dutch Cancer Society (KWF) and the Netherlands Organization for Scientific Research (NWO), and D.S.P. is an EMBO young investigator.

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    Benjamin D. Rowland & Daniel S. Peeper

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National Cancer Institute

breast cancer

colon cancer

gastric cancer

lymphomas

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Epithelial to mesenchymal transition

Loss of epithelial cell polarity and cell–cell contacts with repression of epithelial markers, often associated with acquisition of fibroblastic characteristics.

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Rowland, B., Peeper, D. KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer 6, 11–23 (2006). https://doi.org/10.1038/nrc1780

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