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  • Review Article
  • Published:

The RUNX family: developmental regulators in cancer

Key Points

  • The RUNX transcription factors are key regulators of lineage specification. They are associated with major developmental pathways such as transforming growth factor-β, WNT, Indian hedgehog, Notch, receptor tyrosine kinases and mammalian STE20-like protein kinase (MST)–Yes-associated protein 1 (YAP1).

  • RUNX family members share the evolutionarily conserved Runt domain, which binds to core-binding factor-β (CBFβ) and mediates DNA binding. Tissue-specific and overlapping expression patterns indicate both exclusive and redundant roles for the three RUNX genes in humans.

  • RUNX proteins have key roles in diverse cellular processes such as cell proliferation, differentiation, senescence, apoptosis, epithelial–mesenchymal transition, inflammation, epigenetic memory and DNA repair. RUNX activities are context dependent, can be non-DNA binding and can be dramatically altered by a broad repertoire of protein interacting partners, as well as by post-translational modification events.

  • RUNX proteins exert paradoxical activities in cancer pathogenesis: they are strongly tumour suppressive in some cancers but oncogenic in others. Aberrant expression of RUNX genes is frequently observed in diverse cancer types and has been shown to have major roles in the carcinogenic process.

  • RUNX functions upstream of the ARF–p53 pathway to promote senescence and suppress RAS-induced tumorigenesis.

  • RUNX proteins collaborate with the MYC oncogene to promote lymphoma.

  • The pathogenesis of cancer in epithelial cells is profoundly affected by the dominant role of RUNX in inflammation and its impact on the tumour microenvironment.

Abstract

RUNX proteins belong to a family of metazoan transcription factors that serve as master regulators of development. They are frequently deregulated in human cancers, indicating a prominent and, at times, paradoxical role in cancer pathogenesis. The contextual cues that direct RUNX function represent a fast-growing field in cancer research and could provide insights that are applicable to early cancer detection and treatment. This Review describes how RUNX proteins communicate with key signalling pathways during the multistep progression to malignancy; in particular, we highlight the emerging partnership of RUNX with p53 in cancer suppression.

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Figure 1: Network of RUNX interactions with signalling pathways.
Figure 2: Distribution of somatic mutations in the three human RUNX genes.

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Acknowledgements

Y.I. is supported by the Singapore National Research Foundation under its Translational and Clinical Research Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council, as well as the Singapore Ministry of Education under its Research Centres of Excellence initiative. S.-C.B is supported by a Creative Research Grant (2014R1A3A2030690) from the Korea Research Foundation.

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Glossary

Cleidocranial dysplasia

(CCD). A congenital dominant bone disorder associated with RUNX2 mutations. Individuals with the disorder have skeletal deformities in the collarbone and cranium.

Super-enhancer

A large cluster of DNA regulatory elements that enhances the transcription of genes involved in cell identity and/or tissue type-specific gene expression programmes.

Chief cells

Specialized pepsinogen-secreting glandular cells of the gastric epithelium. They are located at the bottom of the fundic gland in the main body of the stomach.

Spasmolytic polypeptide/trefoil factor family 2 (TFF2)-expressing metaplasia

(SPEM). Precancerous metaplasia of chief cells. TFF2 is usually expressed in the precursor of chief cells, suggesting that SPEM is induced by the transdifferentiation of chief cells.

Li–Fraumeni syndrome

A rare autosomal, familial disorder associated with germline mutations of TP53 and increased cancer susceptibility.

Fanconi anaemia

An autosomal recessive disorder associated with mutations in the Fanconi anaemia family of genes, the products of which are involved in DNA repair. Patients often develop bone marrow failure and are extremely susceptible to cancer development, such as acute myeloid leukaemia.

γH2AX signals

The phosphorylation of member X of the H2A histone family at serine 139, which is an indicator of DNA double-strand breaks.

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Ito, Y., Bae, SC. & Chuang, L. The RUNX family: developmental regulators in cancer. Nat Rev Cancer 15, 81–95 (2015). https://doi.org/10.1038/nrc3877

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