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REVIEWS
The RUNX family: developmental regulators in cancer
Yoshiaki Ito1, SukChul Bae2 and Linda Shyue Huey Chuang1
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.
RUNX transcription factors are essential regulators of diverse developmental processes, with roles in proliferation, differentiation, apoptosis and cell lineage specification. The RUNX family of genes is evolutionarily old, and members have been identified in both simple and complex metazoans, suggesting close involvement of RUNX genes in fundamental biological processes1
(BOX1). RUNX genes were independently identified as a Drosophila melanogaster segmentation gene Runt, as part of the t(8;21) chromosome translocation in acute myeloid leukaemia (AML) and as a subunit of the polyoma-virus enhancer-binding protein 2 (reviewed in REF.1). In
mammals, there are three RUNX genes, RUNX1, RUNX2 and RUNX3, each with distinct tissue-specific expression patterns. Their functions are dependent on cell context and are linked to major developmental pathways, such as those regulated by transforming growth factor- (TGF; reviewed in REF.2), WNT3, Indian hedgehog4, Notch5, receptor tyrosine kinases6 and mammalian STE20-like protein kinase (MST)Yes-associated protein 1 (YAP1)7,8
(FIG.1). RUNX genes are intimately involved in carcino-genesis: RUNX1 mutation in human leukaemia has been extensively studied9. RUNX2 is a bone lineage-specific factor that has been linked to osteosarcoma; the increased expression of RUNX2 in breast and prostate cancer cells that metastasize to the bone indicates protumorigenic and pro-metastatic roles10. RUNX3 inactivation in solid tumours is now firmly established as a causative factor in cancer pathogenesis1.
Proviral insertional mutagenesis in CD2Myc transgenic mice, which overexpress MYC in Tlymphocytes, readily identified all RUNX genes as viral insertional targets: viral-induced overexpression of intact RUNX
proteins was associated with accelerated Tcell lymphomas1113. This discovery of RUNX family members as MYC-collaborating genes considerably affected the RUNX field and highlighted the...