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  • Review Article
  • Published:

Krüppel-like factors in cancer

Key Points

  • The Krüppel-like factors (KLFs) are a family of transcriptional regulators linked by a triple zinc finger DNA-binding domain.

  • In normal tissues, KLFs control a broad number of key cellular processes, including proliferation, differentiation, migration, inflammation and pluripotency.

  • KLF expression and function are altered in a large number of human cancers, and KLFs regulate cancer cell proliferation and apoptosis, metastasis, tumour microenvironment and cancer stem cells.

  • KLFs have context-dependent functions, partly mediated by molecular switches, such as p53, p21 or SIN3 transcription regulator homologue A (SIN3A), alternative splicing and post-translational modifications.

  • KLFs cross-regulate and compensate for each other in cancer, although these functions remain to be fully defined.

  • Understanding the mechanisms of KLF function in cancer will probably lead to new translational discoveries for cancer diagnosis and treatment.

Abstract

Krüppel-like factors (KLFs) are a family of DNA-binding transcriptional regulators with diverse and essential functions in a multitude of cellular processes, including proliferation, differentiation, migration, inflammation and pluripotency. In this Review, we discuss the roles and regulation of the 17 known KLFs in various cancer-relevant processes. Importantly, the functions of KLFs are context dependent, with some KLFs having different roles in normal cells and cancer, during cancer development and progression and in different cancer types. We also identify key questions for the field that are likely to lead to important new translational research and discoveries in cancer biology.

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Figure 1: Structural relationships of KLFs.
Figure 2: p21, p53 and SIN3A are molecular switches for KLF function.
Figure 3: KLF splice variants antagonize wild-type function.
Figure 4: Post-translational modifications alter KLF function.
Figure 5: KLFs control cancer cell proliferation by targeting cell cycle regulators.
Figure 6: KLFs have diverse effects on cancer cells and the tumour microenvironment.

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Acknowledgements

The authors acknowledge support from US National Institutes of Health (NIH) NIDDK R01 DK069984 (to J.P.K.), by NIH NIDDK K99 DK094977 (to M.P.T.) and from the University of Pennsylvania Center for Molecular Studies in Digestive and Liver Diseases (NIH NIDDK P30 DK050306) and NIH NCI P01 CA098101.

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Alterations of the KLFs in cancers (PDF 464 kb)

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Gene targets of the KLFs in cancer (PDF 384 kb)

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Glossary

Cancer stem cells

(CSCs). A subset of cells within a heterogeneous population of cancer cells that are capable of initiating and propagating the tumour.

ApcMin mice

Mice that carry the multiple intestinal neoplasia (Min) point mutation at one Apc allele and that develop intestinal adenomas spontaneously. ApcMin mice are a commonly used model of human familial adenomatous polyposis and human sporadic colorectal cancer.

DMBA and TPA model

A two-stage chemical skin carcinogenesis model using a single dose of the genotoxic carcinogen DMBA, followed by multiple doses of a non-genotoxic tumour-promoter, TPA.

BCR-ABL

A fusion protein that results from the reciprocal translocation between chromosome 9 and chromosome 22 (t(9;22)(q34;q11)) and that is responsible for the induction of chronic myelogenous leukaemia.

Anoikis

Apoptosis triggered by lack of attachment to a substrate.

Epithelial–mesenchymal transition

(EMT). A complex process in which genetic and epigenetic events lead to epithelial cells acquiring a mesenchymal architecture concomitant with increased cell motility. EMT is typically associated with the loss of E-cadherin expression, disruption of cell–cell junctions, and cancer cell invasion and metastasis.

Macrophage polarization

Macrophages can be functionally polarized into M1 and M2 phenotypes. M1 macrophages have a pro-inflammatory role, whereas M2 macrophages have an anti-inflammatory role, promote angiogenesis and favour tumour progression.

Regulatory T cell

(TReg). A member of a population of CD4+FOXP3+CD25high T lymphocytes that seem to have a dual role in cancer progression and accumulate in the tumours and peripheral blood of cancer patients. In some cancers, TReg cells enhance tumour growth by suppressing antitumour immune responses, whereas in other cancers TReg cells limit inflammation that promotes carcinogenesis.

Side population

A subpopulation of cells that, because of increased dye efflux, demonstrates lower staining with the supravital stain Hoechst 33342. Hoechst-low cells are presumed to represent progenitor or stem cells and can be isolated by fluorescence-activated cell sorting.

Pioneer factor

A protein that physically interacts with compacted chromatin, to rapidly facilitate the binding of additional proteins.

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Tetreault, MP., Yang, Y. & Katz, J. Krüppel-like factors in cancer. Nat Rev Cancer 13, 701–713 (2013). https://doi.org/10.1038/nrc3582

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