Abstract
Grainyhead-like (GRHL) factors are essential, highly conserved transcription factors (TFs) that regulate processes common to both natural cellular behaviours during embryogenesis, and de-regulation of growth and survival pathways in cancer. Serving to drive the transcription, and therefore activation of multiple co-ordinating pathways, the three GRHL family members (GRHL1-3) are a critical conduit for modulating the molecular landscape that guides cellular decision-making processes during proliferation, epithelial-mesenchymal transition (EMT) and migration. Animal models and in vitro approaches harbouring GRHL loss or gain-of-function are key research tools to understanding gene function, which gives confidence that resultant phenotypes and cellular behaviours may be translatable to humans. Critically, identifying and characterising the target genes to which these factors bind is also essential, as they allow us to discover and understand novel genetic pathways that could ultimately be used as targets for disease diagnosis, drug discovery and therapeutic strategies. GRHL1-3 and their transcriptional targets have been shown to drive comparable cellular processes in Drosophila, C. elegans, zebrafish and mice, and have recently also been implicated in the aetiology and/or progression of a number of human congenital disorders and cancers of epithelial origin. In this review, we will summarise the state of knowledge pertaining to the role of the GRHL family target genes in both development and cancer, primarily through understanding the genetic pathways transcriptionally regulated by these factors across disparate disease contexts.
Highlights
The best animal models are those that closely recapitulate key aspects of a disease in humans
Mechanistic studies have suggested that defects in Planar Cell Polarity (PCP) [75], insufficient cell proliferation in the hindgut endoderm [116], and abnormal cell function in the non-neural surface ectoderm [116] may underpin defects of Grhl3-mediated neurulation, and like in Grhl2−/− embryos, it is likely that multiple genetic mechanisms driven by disparate target genes underpin these processes
The expression of Cacna1d, Dopa Decarboxylase (Ddc), Flot2 (Flotillin 2) and Xpo1 (Exportin 1) is reduced in the Grhl1-null kidneys, and all these genes have potential GRHL-binding sited in their promoter regions [80]
Summary
The best animal models are those that closely recapitulate key aspects of a disease in humans. Grh can bind to and/or directly activate transcription from the promoters of these genes during the development of neuronal cells. Grhl target genes involved in placental development in mice, as verified by direct promoter binding (ChIP). Grhl and Zeb form a double negative regulatory feedback loop in breast cancer cell lines These genes were down-regulated in kidney collecting ducts lacking Grhl, and were confirmed as direct binding targets via ChIP. IRF6 binds to an enhancer element near the Grhl promoter, and may regulate the development of the periderm in both zebrafish and human keratinocytes. BIOLOGICAL ROLE Grhl binds to the proximal region of the Oct-4 promotor, putatively regulating the transcription of Oct-4 in cell reprogramming and contributing to oral cell carcinoma. GRHL1 binds to the promoters of these genes and directly regulates their expression in non-small cell lung cancer (NSCLC) cells
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