Misregulation of the proline rich homeodomain (PRH/HHEX) protein in cancer cells and its consequences for tumour growth and invasion

Abstract

The proline rich homeodomain protein (PRH), also known as haematopoietically expressed homeobox (HHEX), is an essential transcription factor in embryonic development and in the adult. The PRH protein forms oligomeric complexes that bind to tandemly repeated PRH recognition sequences within or at a distance from PRH-target genes and recruit a variety of PRH-interacting proteins. PRH can also bind to other transcription factors and co-regulate specific target genes either directly through DNA binding, or indirectly through effects on the activity of its partner proteins. In addition, like some other homeodomain proteins, PRH can regulate the translation of specific mRNAs. Altered PRH expression and altered PRH intracellular localisation, are associated with breast cancer, liver cancer and thyroid cancer and some subtypes of leukaemia. This is consistent with the involvement of multiple PRH-interacting proteins, including the oncoprotein c-Myc, translation initiation factor 4E (eIF4E), and the promyelocytic leukaemia protein (PML), in the control of cell proliferation and cell survival. Similarly, multiple PRH target genes, including the genes encoding vascular endothelial growth factor (VEGF), VEGF receptors, Endoglin, and Goosecoid, are known to be important in the control of cell proliferation and cell survival and/or the regulation of cell migration and invasion. In this review, we summarise the evidence that implicates PRH in tumourigenesis and we review the data that suggests PRH levels could be useful in cancer prognosis and in the choice of treatment options.

Hhex induces promyelocyte self-renewal and cooperates with growth factor independence to cause myeloid leukemia in mice

“…1,2 Hhex was first cloned via its expression in hematopoietic tissues, where it is highly expressed in hematopoietic stem cells (HSCs) and progenitors but then undergoes transcriptional downregulation during differentiation, particularly in the T-cell lineage. [3][4][5] Consistent with the function of members of the homeobox gene family, Hhex has been shown to have important developmental roles during embryogenesis.…”

Blood platelets stimulate cancer extravasation through TGFβ-mediated downregulation of PRH/HHEX

“…Both of these mechanisms are likely to contribute to the induction of EMT and to be of relevance in prostate cancer progression. As PRH appears to function as a tumour suppressor in breast cancer cells and some other cancer cells 18 , it is likely that some or all of these mechanisms are important in the context of these diseases.…”

“…The transcription factor PRH/HHEX (proline-rich homeodomain/haematopoietically expressed homeobox) is essential for the formation of many organs during embryonic development 16,17 . PRH is expressed in many tissues in the adult and downregulation of PRH protein expression and/or aberrant subcellular localisation of PRH is associated with breast, prostate, thyroid, and liver tumours 18 . PRH inactivation is common to a number of cancer types but the mechanisms of PRH inactivation vary in different disease states.…”

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects

“…Like many transcription factors PRH can either repress or activate transcription depending on its target gene (see Soufi et al [1] and Gaston et al [40] for lists of PRH target genes) and its partner proteins (shown in Figure 1). For example, PRH represses the Goosecoid, ESM-1, VEGFA, VEGFR-1, VEGFR-2, and thyroglobulin promoters [8,21,23,24].…”

“…In contrast, PRH has been shown to function as an oncoprotein in T-cell lineages and in AML subtypes (reviewed by Gaston et al [40]). In retroviral insertion experiments in mice (Lvis1)-elevated PRH expression is associated with B-cell-and T-cell-derived leukaemias and lymphomas [41,42].…”