PBX3 in Cancer

Abstract

PBX3 is a homeodomain-containing transcription factor of the pre-B cell leukemia (PBX) family, members of which have extensive roles in early development and some adult processes. A number of features distinguish PBX3 from other PBX proteins, including the ability to form specific and stable interactions with DNA in the absence of cofactors. PBX3 has frequently been reported as having a role in the development and maintenance of a malignant phenotype, and high levels of PBX3 tumor expression have been linked to shorter overall survival in cancer. In this review we consider the similarities and differences in the function of PBX3 in different cancer types and draw together the core signaling pathways involved to help provide a better insight into its potential as a therapeutic target.

Keywords: HOX; PBX; PBX3; acute myeloid leukemia; colorectal cancer; gastric cancer; liver cancer; microRNA.

Figure 1

Pre-B cell leukemia (PBX3) is a target and a regulator of multiple signaling pathways. These include the MEK/ERK pathway, and notably tyrosine kinase receptor Flt3. Activation of this pathway represents a positive feedback loop in which increased expression of the Myc transcription factor activates LIN28 expression, which in turn inhibits biogenesis of miR-let-7b, an miR that blocks PBX3 expression post-transcriptionally. PBX3 also increases signaling through the AKT pathway by activating expression of the AKT activator protein, TRIP2. In addition, PBX3 expression increases in response to the signaling through the canonical WNT pathway via the activation of the Snail transcription factor. Activation of PBX3 through these pathways increases epithelial-to-mesenchymal transition (EMT) and hence invasion and metastasis (in part through increasing MMP9, IL6, and HMGA-2 expression) as well as cell survival and proliferation, and can also confer a TIC phenotype through upregulation of the SOX2 and SALL2 transcription factors and voltage-gated calcium channel α2δ1. Dashed lines represent indirect pathways involving multiple steps and additional components.