A tale of TALE, PREP1, PBX1, and MEIS1: Interconnections and competition in cancer

Abstract

We report the latest structural information on PREP1 tumor suppressor, the specific ''oncogene'' and ''tumor suppressive'' signatures of MEIS1 and PREP1, the molecular rules regulating PREP1 and MEIS1 binding to DNA, and how these can change depending on the interaction with PBX1, cell-type, neoplastic transformation, and intracellular concentration. As both PREP1 and MEIS1 interact with PBX1 they functionally compete with each other. PREP1, PBX1, and MEIS1 TALE-class homeodomain transcription factors act in an interdependent and integrated way in experimental tumorigenesis. We also pool together the plethora of data available in human cancer databanks and connect them with the available molecular information. The emerging picture suggests that a similarly basic approach might be used to better dissect and define other oncogenes and suppressors and better understand human cancer.

The genetics and the molecular functions of the PREP1 homeodomain transcription factor

“…In this and many other ChIP-seq studies, Prep1 binds more frequently promoters than enhancers, while Meis1 does the reverse (Blasi et al, 2017). Gene Ontology analysis of the binding sites in the E10.5 embryo shows that the genes bound by Meis1 are highly enriched in the embryonic development categories whereas those bound by Prep1 are enriched in genes more related to basic cell functions (Penkov et al, 2013).…”

“…Gene Ontology analysis of the binding sites in the E10.5 embryo shows that the genes bound by Meis1 are highly enriched in the embryonic development categories whereas those bound by Prep1 are enriched in genes more related to basic cell functions (Penkov et al, 2013). However, it is clear that Prep1 sites differ from cell to cell with only a conserved core set of genes (Blasi et al, 2017;Laurent et al, 2015;Dardaei et al, 2015;Palmigiano et al, 2018). Finally, the binding specificity is also affected by the concentration of the proteins in vivo.…”

“…Biochemical and genetic properties of Prep1, as well as its role in cancer have been reviewed recently (Blasi et al, 2017;Longobardi et al, 2014). Here we will review the role of Prep1 in development and organogenesis as demonstrated by various mutants, mostly in mice.…”

MEIS transcription factors in development and disease

“…PREP1 competes with MEIS1 for dimerization with the shared co-factor PBX1, as demonstrated using several cancer cell lines, including some from individuals with neuroblastoma (Dardaei et al, 2014). When MEIS1 is co-expressed with PREP1, the relative intracellular concentration of both proteins thus determines MEIS1 protein function (Blasi et al, 2017). In addition, like other central oncogenic transcription factors, such as MYC, MEIS1 has recently been linked to activation of a superenhancer (a region comprising multiple enhancers that bind several transcription factors, driving cell-identity transcription).…”

“…Here, we focus on MEIS genes in vertebrates, but do touch upon some invertebrate models for comparison. For a deeper understanding of the roles of other TALE genes, we refer the reader to excellent reviews on Prep1 by Blasi et al (2017) and PBC genes by Selleri et al (2019). We instead discuss recent findings on Meis1, Meis2 and Meis3, focusing on novel advances concerning their varying mechanisms of action and diverse modes of regulation.…”